WO2004014866A1 - Derives d'azaisoquinoline utilises comme inhibiteurs de metalloproteases matricielles - Google Patents

Derives d'azaisoquinoline utilises comme inhibiteurs de metalloproteases matricielles Download PDF

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Publication number
WO2004014866A1
WO2004014866A1 PCT/IB2003/003485 IB0303485W WO2004014866A1 WO 2004014866 A1 WO2004014866 A1 WO 2004014866A1 IB 0303485 W IB0303485 W IB 0303485W WO 2004014866 A1 WO2004014866 A1 WO 2004014866A1
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alkylenyl
substituted
alkyl
phenyl
compound
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PCT/IB2003/003485
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English (en)
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Amy Mae Bunker
Joseph Armand Picard
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Warner-Lambert Company Llc
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Priority to JP2004527200A priority Critical patent/JP2006504665A/ja
Priority to EP03784388A priority patent/EP1539709A1/fr
Priority to AU2003249531A priority patent/AU2003249531A1/en
Priority to CA002495293A priority patent/CA2495293A1/fr
Priority to BR0313724-4A priority patent/BR0313724A/pt
Priority to MXPA05001786A priority patent/MXPA05001786A/es
Publication of WO2004014866A1 publication Critical patent/WO2004014866A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to azaisoquinoline derivatives which inhibit matrix metalloproteinase enzymes and thus are useful for treating diseases resulting from
  • MMP-mediated tissue breakdown such as heart disease, cardiac insufficiency, inflammatory bowel disease, multiple sclerosis, osteo- and rheumatoid arthritis, arthritis other than osteo- or rheumatoid arthritis, heart failure, age-related macular degeneration, chronic obstructive pulmonary disease, asthma, periodontal diseases, psoriasis, atherosclerosis, and osteoporosis.
  • Matrix metalloproteinases (sometimes referred to as MMPs) are naturally occurring enzymes found in most mammals. Over-expression and activation of MMPs, or an imbalance between MMPs and inhibitors of MMPs, have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues.
  • Stromelysin-1 and gelatinase A are members of the MMP family. Other members include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7), collagenase 3 (MMP-13),
  • TNF-alpha converting enzyme TACE
  • TNF-alpha converting enzyme TACE
  • other newly discovered membrane-associated matrix metalloproteinases Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature, 1994;370:61-65.
  • These enzymes have been implicated with a number of diseases which result from breakdown of connective tissue, including such diseases as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis.
  • a method for preventing and treating these and other diseases is now recognized to be by inhibiting matrix metalloproteinase enzymes, thereby curtailing and/or eliminating the breakdown of connective tissues that results in the disease states.
  • MMP inhibitors A major limitation on the use of currently known MMP inhibitors is their lack of specificity for any particular enzyme. Recent data has established that specific MMP enzymes are associated with some diseases, with no effect on others. The MMPs are generally categorized based on their substrate specificity, and indeed the collagenase subfamily of MMP-1, MMP-8, and MMP-13 selectively cleave native interstitial collagens, and thus are associated only with diseases linked to such interstitial collagen tissue. This is evidenced by the recent discovery that MMP-13 alone is over expressed in breast carcinoma, while MMP-1 alone is over expressed in papillary carcinoma (see Chen et al., J. Am.
  • Selective inhibitors of MMP-13 include a compound named WAY-170523, which has been reported by Chen et al., supra., 2000, and other compounds are reported in PCT International Patent Application Publication numbers WO 01/63244; WO 00/09485; WO 01/12611; WO 02/34726; and WO
  • An object of this invention is to provide a group of selective MMP-13 inhibitor compounds characterized as being azaisoquinoline derivatives.
  • This invention provides an azaisoquinoline derived compound defined by Formula I.
  • embodiments of the invention include:
  • R s independently selected from:
  • R 2 is independently selected from:
  • PhenyK -Cs alkylenyl Substituted phenyl-(Ci-C 8 alkylenyl);
  • Each substituted R 1 and R 2 group contains from 1 to 4 substituents, each independently on a carbon or nitrogen atom, independently selected from:
  • R is H or d-C 6 alkyl
  • G is CH 2 ; O, S, S(O); or S(O) 2 ;
  • Each m is an integer of 0 or 1;
  • R 3 and R 4 are independently selected from the groups: H; Ci-Q alkyl;
  • C 3 -C 6 cycloalkyl Substituted C 3 -C 6 cycloalkyl; C 3 -C 6 cycloalkyl- ⁇ rCs alkylenyl); Substituted C 3 -C 6 cycloalkyHQ-Cg alkylenyl); Phenyl;
  • Each substituted R 3 and R 4 group contains from 1 to 4 substituents, each independently on a carbon or nitrogen atom, independently selected from: H 2 N;
  • Ci-Q alkyl Ci-Q alkyl
  • Halo; and HO 2 C; wherein 2 substituents may be taken together with a carbon atom to which they are both bonded to form the group C O;
  • R 5 is H, Ci-C ⁇ alkyl, H 2 N, HO, or halo;
  • n is an integer of from 0 to 3;
  • Q is selected from:
  • W 1 is independently N-R 5 or C(H)R 5 when — is absent, wherein R 5 is as defined above;
  • W 1 is independently N or C-R 5 when — is a bond, wherein R 5 is as defined above;
  • Each W 2 , W 3 , and W 4 is independently N or C-R 5 , wherein R 5 is as defined above; wherein at least 1 of W 1 , W 2 , W 3 , and W 4 is N;
  • each d-Cio bicycloalkyl is a bicyclic carbocyclic ring that contains 8-, 9- , or 10-member carbon atoms which are 5,5-fused, 6,5-fused, or 6,6-fused bicyclic rings, respectively, and wherein the ring is saturated or optionally contains one carbon-carbon double bond;
  • each 8- to 10-membered heterobicycloalkyl is a bicyclic ring that contains carbon atoms and from 1 to 4 heteroatoms independently selected from 2 0, 1 S, 1 S(O), 1 S(O) 2 , 1 N, 4 N(H), and 4 N(C C 6 alkyl), and where
  • each 5-membered heteroaryl contains carbon atoms and from 1 to 4 heteroatoms independently selected from 1 0, 1 S, 1 N(H), 1 N(d-C 6 alkyl), and 4 N
  • each 6-membered heteroaryl contains carbon atoms and 1 or 2 heteroatoms independently selected from N, N(H), and N(d-C 6 alkyl)
  • 5- and 6-membered heteroaryl are monocyclic rings
  • each heterobiaryl contains carbon atoms and from 1 to 4 heteroatoms independently selected from 1 0, 1 S, 1 N(H), 1 N(C C 6 alkyl), and 4 N, and where the 8-, 9-, and 10-membered heterobia
  • each of R 1 and R 2 is independently selected from: 5- or 6-membered heteroaryl-(C 1 -Cg alkylenyl);
  • each of R 1 and R 2 is independently selected from: 5- or 6-membered heteroaryl-(d-Cg alkylenyl); and Substituted 5- or 6-membered heteroaryl-(C 1 -C 8 alkylenyl); wherein each group and each substituent is independently selected.
  • Substituted 8- to 10-membered heterobiaryl-(Cj-Cg alkylenyl); and the other one of R 1 and R 2 is independently selected from: Phenyl-(d-C 8 alkylenyl); and Substituted phenyl-(C 1 -Cg alkylenyl); wherein each group and each substituent is independently selected.
  • R 2 is independently selected from:
  • R 1 is independently selected from: 5- or 6-membered heteroaryl-(C ⁇ -C 8 alkylenyl); Substituted 5- or 6-membered heteroaryl-(d-C 8 alkylenyl); Phenyl-(C r C 8 alkylenyl); and Substituted phenyl -(d-C 8 alkylenyl); and R 2 is independently selected from:
  • V, X, and R are as defined above.
  • Rl is independently selected from:
  • R 2 is independently selected from:
  • Each substituted R 1 and R 2 group contains from 1 to 4 substituents, each independently on a carbon or nitrogen atom, independently selected from: d-C 6 alkyl;
  • R is H or d-C 6 alkyl
  • G is CH 2 ; O, S, S(O); or S(O) 2 ;
  • Each m is an integer of 0 or 1;
  • W 1 is independently N or C-R 5 , wherein R 5 is as defined above;
  • Each W 2 , W 3 , and W 4 is independently N or C-R 5 , wherein R 5 is as defined above; wherein at least 1 of W 1 , W 2 , W 3 , and W 4 is N;
  • each Cg-C 10 bicycloalkyl is a bicyclic carbocyclic ring that contains 8-, 9- , or 10-member carbon atoms which are 5,5-fused, 6,5-fused, or 6,6-fused bicyclic rings-, respectively, and wherein the ring is saturated or optionally contains one carbon-carbon double bond;
  • each 8- to 10-membered heterobicycloalkyl is a bicyclic ring that contains carbon atoms and from 1 to 4 heteroatoms independently selected from 2 0, 1 S, 1 S(O), 1 S(O) 2 , 1 N, 4 N(H), and 4 N(d-C 6 alkyl), and wherein when two O
  • each of R 1 and R 2 is independently selected from: 5- or 6-membered heteroaryl-(C ⁇ -C 8 alkylenyl); and
  • R 1 and R 2 is independently selected from:
  • Substituted phenyl-(d-Cg alkylenyl); and R 2 is independently selected from:
  • R 2 is independently selected from: Phenyl-(C C 8 alkylenyl); and
  • the compound according to Embodiment 54 selected from: 4-[ l-Oxo-7-(3-phenyl-prop- 1-ynyl)- lH-3-azaisoquinolin-2- ylmethyl]benzoic acid tert-butyl ester;
  • the compound according to Embodiment 54 selected from: 7-(3-Phenyl- ⁇ rop-l-ynyl)-2-(4-trifluoromethylbenzyl)-2H-5- azaisoquinolin- 1 -one ; 2-(3-Fluorobenzyl)-7-(3-phenyl-prop-l-ynyl)-2H-5-azaisoquinolin-l-one;
  • the compound according to Embodiment 54 selected from: 4-[l-Oxo-7-(3-phenyl-prop-l-ynyl)-lH-8-azaisoquinolin-2- ylmethyl]benzoic acid methyl ester; 3-[l-Oxo-7-(3-phenyl-prop-l-ynyl)-lH-8-azaisoquinolin-2- ylmethyljbenzoic acid methyl ester; or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent.
  • Embodiment 77 comprising a compound of Formula I according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent.
  • a method for inhibiting an MMP-13 enzyme in an animal comprising administering to the animal an MMP-13 inhibiting amount of a compound of
  • Embodiment 80 The method according to Embodiment 79, wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • 81 A method for treating a disease mediated by an MMP-13 enzyme, comprising administering to a patient suffering from such a disease a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 81 wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating arthritis comprising administering to a patient suffering from an arthritis disease a nontoxic antiarthritic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating osteoarthritis comprising administering to a patient suffering from osteoarthritis a nontoxic effective amount of a compound of
  • Embodiment 85 The method according to Embodiment 85, wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating rheumatoid arthritis comprising administering to a patient suffering from rheumatoid arthritis a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • a method for treating psoriatic arthritis comprising administering to a patient suffering from psoriatic arthritis a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating a cancer comprising administering to a patient suffering from a cancer a nontoxic anti-cancer effective amount of a compound of
  • a method for treating breast carcinoma comprising administering to a patient suffering from breast carcinoma a nontoxic effective amount of a compound of Formula I according to Embodiment 1 , or a pharmaceutically acceptable salt thereof.
  • a method for treating atherosclerosis comprising administering to a patient suffering from atherosclerosis a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 95 wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating inflammation comprising administering to a patient suffering from inflammation a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • a method for treating heart failure comprising administering to a patient suffering from heart failure a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 99 wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating age-related macular degeneration comprising administering to a patient suffering from age-related macular degeneration a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 101 wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • 103 A method for treating chronic obstructive pulmonary disease, comprising administering to a patient suffering from chronic obstructive pulmonary disease a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 103 wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating heart disease comprising administering to a patient suffering from heart disease a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 105 The method according to Embodiment 105, wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating multiple sclerosis comprising administering to a patient suffering from multiple sclerosis a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating psoriasis comprising administering to a patient suffering from psoriasis a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof comprising administering to a patient suffering from psoriasis a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • 110. The method according to Embodiment 109, wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating asthma comprising administering to a patient suffering from asthma a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 111 wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating cardiac insufficiency comprising administering to a patient suffering from cardiac insufficiency a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 113 The method according to Embodiment 113, wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating inflammatory bowel disease comprising administering to a patient suffering from inflammatory bowel disease a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • a method for treating osteoporosis comprising administering to a patient suffering from osteoporosis a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 117 wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • a method for treating periodontal diseases comprising administering to a patient suffering from periodontal diseases a nontoxic effective amount of a compound of Formula I according to Embodiment 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 120 The method according to Embodiment 119, wherein the compound of Formula I is according to any one of Embodiments 2 to 76, or a pharmaceutically acceptable salt thereof.
  • This invention provides compounds defined by Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 , Q, Y, R 2 , R 3 , R 4 , R 5 , and n are as defined above.
  • the invention also provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, as defined above, together with a pharmaceutically acceptable carrier, diluent, or excipient.
  • the invention also provides methods of inhibiting an MMP-13 enzyme in an animal, comprising administering to the animal a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the invention also provides methods of treating a disease mediated by an
  • MMP-13 enzyme in a patient comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, either alone or in a pharmaceutical composition.
  • the invention also provides methods of treating diseases such as heart disease, multiple sclerosis, osteo- and rheumatoid arthritis, arthritis other than osteo- or rheumatoid arthritis, cardiac insufficiency, inflammatory bowel disease, heart failure, age-related macular degeneration, chronic obstructive pulmonary disease, asthma, periodontal diseases, psoriasis, atherosclerosis, and osteoporosis in a patient, comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof, either alone or in a pharmaceutical composition.
  • diseases such as heart disease, multiple sclerosis, osteo- and rheumatoid arthritis, arthritis other than osteo- or rheumatoid arthritis, cardiac insufficiency, inflammatory bowel disease, heart failure, age-related macular degeneration, chronic obstructive pulmonary disease, asthma, periodontal diseases, psoriasis, atherosclerosis, and osteoporosis in a patient, comprising administer
  • the invention also provides combinations, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with another pharmaceutically active component as described.
  • the groups of Formula I include "Ci -Cg alkyl" groups.
  • C ⁇ -Cg alkyl groups are straight and branched carbon chains having from 1 to 6 carbon atoms.
  • Examples of C -Cg alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2,2-dimethylethyl, 1-pentyl, 2-pentyl, 2,2-dimethylpropyl, and 1 -hexyl.
  • substituted C ⁇ -C6 alkyl means a C ⁇ -C6 alkyl group as defined above that is substituted with from 1 to 4 substituents independently selected from the list above.
  • substituted C ⁇ -Cg alkyl groups include CH 2 OH, CF 2 OH, CH2C(CH 3 ) 2 C ⁇ 2CH 3 , CF 3 , C(O)CF 3 , C(O)- CH 3 , (CH 2 )4-S-CH 3 , CH(CO 2 H)CH2CH 2 C(O)NMe2, (CH 2 )5NH-C(O)-NH 2 ,
  • C2-C alkenyl means a straight or branched, unsubstituted hydrocarbon group having from 2 to 6 carbon atoms and 1 or 2 carbon-carbon double bonds, and include allenyl groups.
  • Typical examples of C2-C.5 alkenyl groups include ethenyl, 1-propen-l-yl, l-propen-2-yl, 2-propen-l-yl, l-buten-3-yl, 2-penten-2-yl, and l-hexen-6-yl.
  • substituted C2-C6 alkenyl means a C2-C6 alkenyl as defined above, which is substituted with from 1 to 4 substituents independently selected from the list above.
  • C2-Cg alkynyl means a straight or branched, unsubstituted hydrocarbon group having from 2 to 6 carbon atoms and 1 or 2 carbon-carbon triple bonds. Typical examples of C2-C6 alkynyl groups include ethenyl,
  • substituted C2-Cg alkynyl means a C2-Cg alkynyl as defined above, which is substituted with from 1 to 4 substituents independently selected from the list above.
  • substituted C2-C ⁇ alkynyl groups include C ⁇ CCH 2 OH, C- ⁇ CF, CH 2 C ⁇ C-(CH2)2CF 2 OH, C* ⁇ C-CH 2 CO 2 CH3,
  • C3-C6 cycloalkyl means an unsubstituted cyclic hydrocarbon group having from 3 to 6 carbon atoms.
  • C 3 -C 6 cycloalkyl may optionally contain one carbon-carbon double bond.
  • the group C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-4-yl, and cyclohexyl.
  • substituted C3-C6 cycloalkyl means a C3-C5 cycloalkyl as defined above, which is substituted with from 1 to 4 substituents independently selected from the list above.
  • substituted C3-C5 cycloalkyl groups include 1-hydroxy-cyclopropyl, cyclobutanon-3-yl, 3-(3-phenyl-ureido)- cyclo ⁇ ent-1-yl, and 4-carboxy-cyclohexyl.
  • 3- to 6-membered heterocycloalkyl means an unsubstituted saturated cyclic group having carbon atoms and 1 or 2 heteroatoms independently selected from 2 0, 1 S, 1 S(O), 1 S(O) 2 , 1 N, 2 N(H), and 2 N(C ⁇ -C6 alkyl), wherein when two O atoms or one O atom and one S atom are present, the two O atoms or one O atom and one S atom are not bonded to each other.
  • 3- to 6-membered heterocycloalkyl may contain one carbon-carbon or carbon- nitrogen double bond.
  • Illustrative examples of 3- to 6-membered heterocycloalkyl includes aziridin-1-yl, l-oxa-cyclobutan-2-yl, tetrahyrdofuran-3-yl, morpholin-4- yl, 2-thiacyclohex-l-yl, 2-oxo-2-thiacyclohe-l-yl, 2,2-dioxo-2-thiacyclohex-l-yl, and 4-methyl-piperazin-2-yl.
  • substituted 3- to 6-membered heterocycloalkyl means a 3- to 6-membered heterocycloalkyl as defined above, which is substituted with from 1 to 4 substituents independently selected from the list above.
  • substituted 3- to 6-membered heterocycloalkyl include 2-hydroxy- aziridin-1-yl, 3-oxo-l-oxacyclobutan-2-yl, 2,2-dimethyl-tetrahydrofuran-3-yl, 3- carboxy-morpholin-4-yl, and l-cyclopropyl-4-methyl-piperazin-2-yl.
  • d-Cg alkylenyl means a saturated hydrocarbon diradical that is straight or branched and has from 1 to 8 carbon atoms.
  • d-C 8 alkylenyl having from 2 to 8 carbon atoms may optionally independently contain one carbon- carbon double bond.
  • Illustrative examples of d-C 8 alkylenyl include CH 2 ,
  • 1- to 8-membered heteroalkylenyl means a saturated diradical chain that is straight or branched and contains from 1 to 7 carbon atoms and 1 heteroatom selected from O, S, N(H), and N(d-C 6 alkyl).
  • 2- to 8-membered heteroalkylenyl, having from 2 to 8 chain atoms, may optionally independently contain one carbon-carbon double bond.
  • cycloalkyl-(d-C 8 alkylenyl) means a C 3 -C 5 cycloalkyl, as defined above, bonded through a d-d alkylenyl, as defined above.
  • Illustrative examples of C 3 -C 6 cycloalkyl-(d-Cg alkylenyl include cyclopropylmethyl, l-cyclopentyl-hex-2-yl, and 2-cyclobutyl-but-2-yl.
  • Substituted C 3 -C 6 cycloalkyl-(d-C 8 alkylenyl) means a C 3 - C cycloalkyl- ⁇ ! -Cg alkylenyl), as defined above, substituted on C 3 -C 6 cycloalkyl and or d-Cg alkylenyl with from 1 to 4 substituents, as defined above.
  • Illustrative examples of substituted C 3 -C 6 cycloalkyHd-Cg alkylenyl include cyclopropylcarbonyl and l-(l-aminomethyl-cyclopentyl)-hex-2-yl.
  • C 5 or C 6 cycloalkyl-(C 1 -Cg alkylenyl) means a cyclopentyl or cyclohexyl bonded through a d-Cg alkylenyl, as defined above, wherein the cycloalkyl optionally contains 1 carbon-carbon double bond.
  • Substituted or C 6 cycloalkyl-(C 1 -Cg alkylenyl) means a substituted cyclopentyl or cyclohexyl, wherein the substituents are as defined above, bonded through a d-C 8 alkylenyl, as defined above, wherein the cycloalkyl optionally contains 1 carbon-carbon double bond.
  • Cg-C 10 bicycloalkyl-(C 1 -Cg alkylenyl) means a cyclopentyl or cyclohexyl fused to another cyclopentyl or cyclohexyl to give a 5,5-, 5,6-, or
  • Substituted C 8 -do bicycloalkyl-(d-Cg alkylenyl) means a Cg-do bicycloalkyl, as defined above, substituted with from 1 to 4 substituents, as defined above, bonded through a d-Cg alkylenyl, as defined above.
  • 5- or 6-membered heterocycloalkyl-(C 1 -C 8 alkylenyl) means a 5- or 6-membered ring containing carbon atoms and 1 or 2 heteroatoms selected from 1 0, 1 S, 1 N, 2 N(H), and 2 N(d-Q alkyl), bonded through a d-C 8 alkylenyl, as defined above.
  • Substituted 5- or 6-membered heterocycloalkyl-(C 1 -C 6 alkylenyl) means a 5- or 6-membered heterocycloalkyl, as defined above, substituted with from 1 to 4 substituents, as defined above, bonded through a d- alkylenyl, as defined above.
  • the phrase "8- to 10-membered heterobicycloalkyl-(d-Cg alkylenyl)" means a 5- or 6-membered ring fused to another 5- or 6-membered ring to give a 5,5-, 5,6-, or 6,6-fused bicyclic group containing carbon atoms and from 1 to 4 heteroatoms independently selected from 2 0, 1 S, 1 S(O), 1 S(O) 2 , 1 N, 4 N(H), and 4 N(C 1 -C 6 alkyl), bonded through a d-Cg alkylenyl, as defined above, wherein the bicycloalkyl optionally contains 1 carbon-carbon double bond or 1 carbon-nitrogen double bond.
  • Substituted 8- to 10-membered heterobicycloalkyl-(C 1 -C 6 alkylenyl) means an 8- to 10-membered heterobicycloalkyl, as defined above, substituted with from 1 to 4 substituents, as defined above, bonded through a d- C 8 alkylenyl, as defined above.
  • 3- to 6-membered heterocycloalkyl-(C 1 -Cg alkylenyl) means a 3- to 6-membered heterocycloalkyl, as defined above, bonded through a d-Cg alkylenyl, as defined above.
  • Substituted 3- to 6-membered heterocycloalkyl-(C 1 -Cg alkylenyl) means a substituted 3- to 6-membered heterocycloalkyl, as defined above, bonded through a Ci-Cg alkylenyl, as defined above.
  • Phenyl-(C 1 -C 8 alkylenyl) means a phenyl group bonded through a d-Cg alkylenyl diradical, wherein Ci-Cg alkylenyl is as defined above.
  • phenyl-(C 1 -C 8 alkylenyl) include benzyl, 2-phenylethyl, 1-phenyl-pro ⁇ -l-yl, and 3-phenyl-heptyl.
  • Substituted phenyHd-Cg alkylenyl means a phenyl-(C 1 -Cg alkylenyl) as defined above, which is substituted on phenyl and/or d-Cg alkylenyl with from 1 to 4 substituents independently selected from the list above.
  • substituted phenyl-(C ⁇ -Cg alkylenyl) include 4-fluoro- phenylmethyl, 2-(4-carboxy-phenyl)-ethyl, 1 -(2,4-dimethoxy-phenyl)-2-oxo- propyl, and l-phenyl-5,5-difluoro-oct-3-yl.
  • the term "naphthyl" includes 1-naphthyl and 2-napthyl.
  • Naphthyl-(d-C 8 alkylenyl) means a naphthyl group as defined above bonded through a d-C 8 alkylenyl diradical, wherein C ⁇ -C 8 alkylenyl is as defined above.
  • Illustrative examples of naphthyl-(C 1 -C 8 alkylenyl) include naphth-1-ylmethyl, 2-(naphth-l-yl)ethyl, and 3-(naphth-2-yl)-l-he ⁇ tyl.
  • Substituted naphthyl-(C r C 8 alkylenyl) means a naphthyl - (Ci-Cs alkylenyl) as defined above, which is substituted on naphthyl and/or d-C 8 alkylenyl with from 1 to 4 substituents independently selected from the list above.
  • substituted phenyl-(C ⁇ -C 8 alkylenyl) include 4-fluoro- (naphth-l-yl)methyl, 2-(4-carboxy-(naphth-l-yl))-ethyl, l-(2,4-dimethoxy-
  • 5- or 6-membered heteroaryl means a 5-membered, monocyclic heteroaryl having carbon atoms and from 1 to 4 heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1 N(d-C 6 alkyl), and 4 N, or a 6-membered, monocyclic heteroaryl having carbon atoms and 1 or 2 heteroatoms selected from 2 N, and wherein:
  • 5-membered, monocyclic heteroaryl means a 5-membered, monocyclic, aromatic ring group as defined above having carbon atoms and from 1 to 4 heteroatoms selected from 1 O, 1 S, 1 N(H), 1 N(d-C 6 alkyl), and 4 N.
  • Illustrative examples of a 5-membered, monocyclic heteroaryl include thiophen-2-yl, furan-2-yl, pyrrol-3-yl, pyrrol-1-yl, imidazol-4-yl, isoxazol- 3-yl, oxazol-2-yl, thiazol-4-yl, tetrazol-1-yl, l,2,4-oxadiazol-3-yl, 1,2,4-triazol- 1-yl, and pyrazol-3-yl; and
  • 6-membered, monocyclic heteroaryl means a 6-membered, monocyclic, aromatic ring group as defined above having carbon atoms and 1 or 2 N.
  • Illustrative examples of a 6-membered, monocyclic heteroaryl include pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyridazin-4-yl, and pyrazin- 2-yl.
  • 8- to 10-membered heterobiaryl means an 8-membered, 5,5- fused bicyclic heteroaryl, a 9-membered, 6,5-fused bicyclic heteroaryl, or a
  • 10-membered, 6,6-fused bicyclic heteroaryl having carbon atoms and from 1 to 4 heteroatoms independently selected from 1 0, 1 S, 1 N(H), 1 N(d-C 6 alkyl), and 4 N, wherein at least one of the 2 fused rings is aromatic, and wherein when the O and S atoms both are present, the O and S atoms are not bonded to each other, which are as defined below:
  • 8-membered, 5,5-fused bicyclic heteroaryl means a an 8-membered aromatic, fused-bicyclic ring group as defined above having carbon atoms and from 1 to 4 heteroatoms selected from 1 O, 1 S, 1 N(H), 1 N(C ⁇ - C 6 alkyl), and 4 N.
  • Illustrative examples of an 8-membered, fused-bicyclic heteroaryl include
  • 9-membered, 6,5-fused bicyclic heteroaryl means a 9-membered aromatic, fused-bicyclic ring group as defined above having carbon atoms and from 1 to 4 heteroatoms selected from 1 0, 1 S, 1 N(H), 1 N(d-d alkyl), and 4 N.
  • Illustrative examples of a 9-membered, fused-bicyclic heteroaryl include indol-2-yl, indol-6-yl, iso-indol-2-yl, benzimidazol-2-yl, benzimidazol-1-yl, benztriazol-1-yl, benztriazol-5-yl, benzoxazol-2-yl, benzothiophen-5-yl, and benzofuran-3-yl; and
  • 10-membered, 6,5-fused bicyclic heteroaryl means a 10-membered aromatic, fused-bicyclic ring group as defined above having carbon atoms and from 1 to 4 heteroatoms selected from 1 0, 1 S, 1 N(H), 1 N(d-C 6 alkyl), and 4 N.
  • Illustrative examples of a 10-membered, fused-bicyclic heteroaryl include quinolin-2-yl, isoquinolin-7-yl, and benzopyrimidin-2-yl.
  • substituted 5- or 6-membered heteroaryl and “substituted 8- to 10-membered heterobiaryl” means a 5- or 6-membered heteroaryl, as defined above, or an 8- to 10-membered heterobiaryl, as defined above, respectively, which is substituted on a carbon (CH) atom, and or nitrogen [N(H)] atom in the case of 5-, 8- to 10-membered heterobiaryl, with from 1 to 4 substituents independently selected from the list above.
  • substituted 5-membered, monocyclic heteroaryl groups include 2-hydroxy-oxoazol-4-yl, 5-chloro-thiophen-2-yl, l-methylimidazol-5-yl, l-propyl-pyrrol-2-yl, l-acetyl-pyrazol-4-yl, 1-methyl- l,2,4-triazol-3-yl, and 2-hexyl-tetrazol-5-yl.
  • substituted 6-membered, monocyclic heteroaryl groups include 4-acetyl-pyridin-2-yl, 3-fluoro-pyridin-4-yl, 5-carboxy-pyrimidin- 2-yl, 6-tertiary butyl-pyridazin-4-yl, and 5-hdyroxymethyl-pyrazin-2-yl.
  • substituted 8-membered, 5,5-fused bicyclic heteroaryl include:
  • substituted 9-membered, 5,6-fused bicyclic heteroaryl include 3-(2-aminomethyl)-indol-2-yl, 2-carboxy-indol-6-yl, 1-
  • substituted 10-membered, 6,6-fused bicyclic heteroaryl include 5,7-dichloro-quinolin-2-yl, isoquinolin-7-yl-l -carboxylic acid ethyl ester, and 3-bromo-benzopyrimidin-2-yl.
  • 5- or 6-membered heteroaryl-(C ⁇ -C 8 alkylenyl) means a 5- or 6-membered heteroaryl, as defined above, bonded through a Ci-Cg alkylenyl, as defined above.
  • Substituted 5- or 6-membered heteroaryl -(d-Cg alkylenyl) means a 5- or 6-membered heteroaryl-(d-Cg alkylenyl), as defined above, which is substituted on 5- or 6-membered heteroaryl and/or Ci-Cg alkylenyl with from 1 to 4 substituents independently selected from the list above.
  • substituted 5-membered heteroaryl-(C ⁇ -Cg alkylenyl) groups include 2-hydroxy-oxoazol-4-ylmethyI, 4-(5-chloro-thiophen-2- yl)-hex-l-yl, and 2-tetrazol-5-yloctyl.
  • substituted 6-membered heteroaryl-(C 1 -Cg alkylenyl) groups include 4-acetyl-pyridin-2-ylmethyl, 7-(3-fluoro-pyridin-4-yl)- hept-2-yl, and 2-(5-hdyroxymethyl-pyrazin-2-yl)-l,l-difluoro-2-hydroxy-prop-2- yi-
  • the phrase "8- to 10-membered heterobiaryl-(C ⁇ -Cg alkylenyl)" means an
  • Substituted 8- to 10-membered heterobiaryl-(C 1 -C 8 alkylenyl) means an 8- to 10-membered heterobiaryl-(C 1 -C 8 alkylenyl), as defined above, which is substituted on 8- to 10-membered heterobiaryl and/or Ci-
  • substituted 8-membered heterobiaryl-(C 1 -Cg alkylenyl) include:
  • substituted 9-membered heterobiaryl-(C ⁇ -Cg alkylenyl) include 3-(2-aminomethyl)-indol-2-ylmethyl, and 1- ( 1 -(2,6-dichlorophenylmethyl)-benzpyrazol-3 -yl)-prop3 -yl .
  • substituted 10-membered heterobiaryl-(C 1 -Cg alkylenyl) include 5,7-dichloro-quinolin-2-ylmethyl, and 5-(3-bromo- benzopyrimidin-2-yl)-oct-2-yl .
  • (d-C 6 alkyl)-O means a d-C 6 alkyl group, as defined above, bonded through an oxygen atom.
  • (d-C 6 alkyl)-S means a d-C 6 alkyl group, as defined above, bonded through an sulfur atom.
  • (d-C 6 alkyl)-S(O) 2 means a C ⁇ -C 6 alkyl group, as defined above, bonded through a sulfur atom, which sulfur atom is substituted with two oxygen atoms.
  • (d-C 6 alkyl)-N(H) means a d-C 6 alkyl group, as defined above, bonded through a nitrogen atom, which is bonded to a hydrogen atom.
  • (C ⁇ -C 6 alkyl) 2 -N means two independently selected d-C 6 alkyl groups, as defined above, including cyclic groups wherein the two d-C 6 alkyl groups are taken together with the nitrogen atom to which they are both bonded to form a 5- or 6-membered heterocycloalkyl, bonded through a nitrogen atom.
  • (Ci-C ⁇ alkyl)-OC(O) means a C]-C 6 alkyl, as defined above, bonded through an oxygen atom-carbonyl carbon atom.
  • the phase "(C C 6 alkyl)-C(O)O-(C 1 -C 8 alkylenyl) m ", wherein m is an integer of 0 or 1, means when, m is 0, a d-C 6 alkyl group, as defined above, bonded through a carbonyl carbon atom-oxygen atom, and, when m is 1, a C ⁇ -C 6 alkyl group, as defined above, bonded through a carbonyl carbon atom-oxygen atom-(d-C 8 alkylenyl), wherein Ci-Cg alkylenyl is as defined above.
  • H 2 NS(O) 2 -(d-Cg alkylenyl) means an amino bonded through a sulfur atom-(d-Cg alkylenyl), wherein the Ci-C alkylenyl is as defined above and the sulfur atom is bonded to two oxygen atoms.
  • (d-C 6 alkyl)-N(H)S(O) 2 -(d-C 8 alkylenyl) m wherein m is an integer of 0 or 1, means, when m is 0, a d-C 6 alkyl, as defined above, bonded through a nitrogen atom-sulfur atom, and, when m is 1, a d-C 6 alkyl, as defined above, bonded through a nitrogen atom-sulfur atom-(d-Cg alkylenyl), wherein the nitrogen atom is bonded to a hydrogen atom, the sulfur atom is bonded to two oxygen atoms, and Ci-Cg alkylenyl is as defined above.
  • (d-C 6 alkyl) 2 -NS(O) 2 -(d-C 8 alkylenyl) m means, when m is 0, two d-C 6 alkyl groups, as defined above, including cyclic groups wherein the two C ⁇ -C 6 alkyl groups are taken together with the nitrogen atom to which they are both bonded to form a 5- or 6-membered heterocycloalkyl, each bonded through a nitrogen atom-sulfur atom, and, when m is 1, two Cj-C 6 alkyl groups, as defined above, each bonded through a nitrogen atom-sulfur atom-(Ci-Cg alkylenyl), wherein the nitrogen atom is bonded to a hydrogen atom, the sulfur atom is bonded to two oxygen atoms, and Ci-Cg alkylenyl is as defined above.
  • 3- to 6-membered heterocycloalkyl-(G) m wherein m is an integer of 0 or 1, means, when m is 0, a 3- to 6-membered heterocycloalkyl, as defined above, and, when m is 1, a 3- to 6-membered heterocycloalkyl, as defined above, bonded through a group G, as defined above.
  • Substituted 3- to 6-membered heterocycloaIkyl-(G) m wherein m is an integer of 0 or 1, means, when m is 0, a substituted 3- to 6- membered heterocycloalkyl, as defined above, and, when m is 1, a substituted 3- to 6-membered heterocycloalkyl, as defined above, bonded through a group G, as defined above.
  • Substituted 5- or 6-membered heteroaryl-(G) m wherein m is an integer of 0 or 1, means, when m is 0, a substituted 5- or 6-membered heteroaryl, as defined above, and, when m is 1, a substituted 5- or 6-membered heteroaryl, as defined above, bonded through a group G, as defined above.
  • Phenyl-O-(d-C 8 alkylenyl) means a phenyl bonded through an oxygen atom, which is bonded through a d-C 8 alkylenyl, wherein d-Cg alkylenyl is as defined above.
  • phenyl-O-(Ci-Cs alkylenyl) include phenoxymethyl and 2-phenoxyethyl.
  • Substituted phenyl-O-(C 1 -C 8 alkylenyl) means a phenyl-O- (Ci-C ⁇ alkylenyl) group, as defined above, that is substituted with from 1 to 4 substituents as defined above for R 2 .
  • Illustrative examples of substituted phenyl- O-(Ci-Cs alkylenyl) include 4-fluorophenoxymethyl and 2-phenoxy- methylcarbonyl.
  • Phenyl-S-(Ci-Cs alkylenyl) means a phenyl bonded through an sulfur atom, which is bonded through a d- alkylenyl, wherein Ci-Cg alkylenyl is as defined above.
  • phenyl-S-(C 1 -C 8 alkylenyl) include thiophenoxymethyl and 2-thiophenoxyethyl.
  • Substituted phenyl-S-(d-C 8 alkylenyl) means a phenyl-S-(C ⁇ - C 8 alkylenyl) group, as defined above, that is substituted with from 1 to 4 substituents as defined above for R 2 .
  • Illustrative examples of substituted phenyl-S- (d-Cg alkylenyl) include 4-fluorothiophenoxymethyl and 2-thiophenoxy- methylcarbonyl.
  • Phenyl-S(O)-(d-C 8 alkylenyl) means a phenyl bonded through an sulfur atom, which is bonded through a d-C 8 alkylenyl, wherein d-C 8 alkylenyl is as defined above and the sulfur atom is also bonded to an oxygen atom.
  • Substituted phenyl-S(O)-(d-C 8 alkylenyl) means a phenyl- S(O)-(Ci-Cs alkylenyl) group, as defined above, that is substituted with from 1 to 4 substituents as defined above for R .
  • Phenyl-S(O) -(Ci-C 8 alkylenyl) means a phenyl bonded through an sulfur atom, which is bonded through a Ci-Cg alkylenyl, wherein Ci-Cg alkylenyl is as defined above and the sulfur atom is also bonded to two oxygen atoms.
  • Substituted phenyl-S(O) 2 -(Ci-C 8 alkylenyl) means a phenyl- S(O) 2 -(C]-C 8 alkylenyl) group, as defined above, that is substituted with from 1 to 4 substituents as defined above for R 2 .
  • substituted phenyl-S(O) 2 -(Ci-C 8 alkylenyl) means a phenyl- S(O) 2 -(C]-C 8 alkylenyl) group, as defined above, that is substituted with from 1 to 4 substituents as defined above for R 2 .
  • (C ⁇ -C 6 alkyl)-S(O) 2 -N(H)-C(O)-(d-C 8 alkylenyl) m means, when m is 0, a d-d alkyl group, as defined above, bonded through a sulfur atom, which is bonded through a nitrogen atom, which is bonded through a carbon atom, wherein the sulfur atom is bonded to two oxygen atoms, the nitrogen atom is bonded to a hydrogen atom, and the carbon atom is doubly bonded to an oxygen atom to form a carbonyl group; and when m is 1, the term means a d-C 6 alkyl group, as defined above, bonded through a sulfur atom, which is bonded through a nitrogen atom, which is bonded through a carbon atom, which is bonded through a d-Cg alkylenyl group, as defined above, wherein the sulfur atom is bonded
  • (d-C 6 alkyl)-C(O)-N(H)-S(O) 2 -(C ⁇ -C 8 alkylenyl) m means, when m is 0, a C ⁇ -C 6 alkyl group, as defined above, bonded through a carbon atom, which is bonded through a nitrogen atom, which is bonded through a sulfur atom, wherein the sulfur atom is bonded to two oxygen atoms, the nitrogen atom is bonded to a hydrogen atom, and the carbon atom is doubly bonded to an oxygen atom to form a carbonyl group; and when m is 1, the term means a d-C 6 alkyl group, as defined above, bonded through a carbon atom, which is bonded through a nitrogen atom, which is bonded through a sulfur atom, which is bonded through a Ci-Cg alkylenyl group, as defined above, wherein the sulfur atom is bonded
  • Preferred substituents for substituted phenyl, substituted naphthyl (i.e., substituted 1-naphthyl or substituted 2-naphthyl), and preferred substituents at carbon atoms for substituted 5-membered, monocyclic heteroaryl, substituted 6-membered, monocyclic heteroaryl, and substituted 9- or 10-membered, fused- bicyclic heteroaryl are C1-C4 alkyl, halo, OH, O-C1-C4 alkyl,
  • substituents are 1,2-methylenedioxy, methoxy, ethoxy, -O-C(O)CH3, carboxy, carbomethoxy, and carboethoxy.
  • 1,2-methylenedioxy means the diradical group -O-CH2-O-, wherein the substituent 1,2-methylenedioxy is bonded to adjacent carbon atoms of the group which is substituted to form a 5-membered ring.
  • groups substituted by 1,2-methylenedioxy include l,3-benzoxazol-5-yl of formula B
  • a fused-bicyclic group is a group wherein two ring systems share two, and only two, atoms.
  • heteroaryl or heterocycloalkyl may not contain two ring atoms bonded to each other which atoms are oxygen and/or sulfur atoms.
  • heteroatom includes O, S, S(O), S(O) 2 , N, N(H), and N(C ⁇ -C 6 alkyl).
  • halo includes fluoro, chloro, bromo, and iodo.
  • amino means NH2.
  • two adjacent, substantially sp 2 carbon atoms means carbon atoms that comprise a carbon-carbon double bond that is capable of being substituted on each carbon atom, wherein the carbon-carbon double bond is contained in an aromatic or nonaromatic, cyclic or acyclic, or carbocyclic or heterocyclic group.
  • tertiary organic amine examples include triethylamine, diisopropylethylamine, benzyl diethylamino, dicyclohexylmethyl-amine, l,8-diazabicycle[5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane (TED), and l,5-diazabicycle[4.3.0]non-5-ene.
  • DBU diisopropylethylamine
  • benzyl diethylamino dicyclohexylmethyl-amine
  • TED l,4-diazabicyclo[2.2.2]octane
  • l,5-diazabicycle[4.3.0]non-5-ene examples include triethylamine, diisopropylethylamine, benzyl diethylamino, dicyclohexylmethyl-amine, l,8-
  • composition means a composition suitable for administration in medical or veterinary use.
  • admixed and the phrase “in admixture” are synonymous and mean in a state of being in a homogeneous or heterogeneous mixture. Preferred is a homogeneous mixture.
  • patient means a mammal.
  • Preferred patients are humans, cats, dogs, cows, horses, pigs, and sheep.
  • animal means a mammal, as defined above.
  • Preferred animals include humans, cats, dogs, horses, pigs, sheep, cows, monkeys, rats, mice, guinea pigs, and rabbits.
  • mammal includes humans, companion animals such as cats and dogs, primates such as monkeys and chimpanzees, and livestock animals such as horses, cows, pigs, and sheep.
  • livestock animals refers to domesticated quadrupeds, which includes those being raised for meat and various byproducts, e.g., a bovine animal including cattle and other members of the genus Bos, a porcine animal including domestic swine and other members of the genus Sus, an ovine animal including sheep and other members of the genus Ovis, domestic goats and other members of the genus Capra; domesticated quadrupeds being raised for specialized tasks such as use as a beast of burden, e.g., an equine animal including domestic horses and other members of the family Equidae, genus Equus, or for searching and sentinel duty, e.g., a canine animal including domestic dogs and other members of the genus Canis; and domesticated quadrupeds being raised primarily for recreational purposes, e.g., members of Equus and Canis, as well as a feline animal including domestic cats and other members of the family
  • anticancer effective amount means an amount of invention compound, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, sufficient to inhibit, halt, or cause regression of the cancer being treated in a particular patient or patient population.
  • an anticancer effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular cancer and patient being treated.
  • anti-arthritic effective amount means an amount of invention compound, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, sufficient to inhibit, halt, or cause regression of the arthritis being treated in a particular patient or patient population.
  • an anti-arthritic effective amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United
  • MMP-13 inhibiting amount means an amount of invention compound, or a pharmaceutically acceptable salt thereof, or a tautomer thereof, sufficient to inhibit an enzyme matrix metalloproteinase-13, including a truncated form thereof, including a catalytic domain thereof, in a particular animal or animal population.
  • an MMP-13 inhibiting amount can be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular MMP-13 enzyme and patient being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration, is within the level of ordinary skill in the pharmaceutical and medical arts, and is described below.
  • phrases "effective amount” and “therapeutically effective amount” are synonymous and mean an amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof, sufficient to effect an improvement of the condition being treated when administered to a patient suffering from a disease that is mediated by MMP-13 and optionally from 0 to 12 additional MMP enzymes.
  • tautomer means a form of invention compound existing in a state of equilibrium with an isomeric form of the invention compound, wherein the invention compound is able to react according to either form by virtue of the ability of the forms to interconvert by isomerization in situ, including in a reaction mixture, in an in vitro biological assay, or in vivo.
  • (E) means Delta, and designates that the conformation about the double bond to which the term refers is the conformation having the two higher ranking substituent groups, as determined according to the Cahn-Ingold- Prelog ranking system, on opposite sides of the double bond.
  • the SI' site of MMP-13 was previously thought to be a grossly linear channel which contained an opening at the top that allowed an amino acid side chain from a substrate molecule to enter during binding, and was closed at the bottom.
  • the SI' site is actually composed of an SI' channel angularly connected to a newly discovered pocket which applicant calls the SI" site.
  • the SI" site is open to solvent at the bottom, which can expose a functional group of Applicants' invention compounds to solvent.
  • the ST site of the MMP-13 enzyme can now be thought of as being like a sock with a hole in the toes, wherein the SI' channel is the region from approximately the opening to the ankle, and the SI" site is the foot region below the ankle, which foot region is angularly connected to the ankle region. More particularly, the SI' channel is a specific part of the SI' site and is formed largely by Leu218, Val219, His222 and by residues from Leu239 to Tyr244.
  • the SI" binding site which has been newly discovered is defined by residues from Tyr246 to Pro255.
  • the SI" site contains at least two hydrogen bond donors and aromatic groups which interact with an invention compound.
  • the SI site could be a recognition site for triple helix collagen, the natural substrate for MMP-13. It is possible that the conformation of the SI" site is modified only when an appropriate compound binds to MMP-13, thereby interfering with the collagen recognition process. This newly discovered pattern of binding offers the possibility of greater selectivity than what is achievable with the binding pattern of known selective inhibitors of MMP-13, wherein the known binding pattern requires ligation of the catalytic zinc atom at the active site and occupation the SI' channel, but not the SI" site.
  • Thr245" means threonine 245 of an MMP-13 enzyme.
  • Thr247 means threonine 247 of an MMP-13 enzyme.
  • Metal253 means methionine 253 of an MMP-13 enzyme.
  • His251 means histidine 251 of an MMP-13 enzyme. It should be appreciated that the matrix metalloproteinases include, but are not limited to, the following enzymes:
  • MMP-1 also known as interstitial collagenase, collagenase- 1, or fibroblast-type collagenase
  • MMP-2 also known as gelatinase A or 72 kDa Type IV collagenase
  • MMP-3 also known as stromelysin or stromelysin-1
  • MMP-7 also known as matrilysin or PUMP-1
  • MMP-8 also known as collagenase-2, neutrophil collagenase or polymorphonuclear-type ("PMN-type") collagenase
  • PMN-type polymorphonuclear-type
  • MMP-9 also known as gelatinase B or 92 kDa Type IN collagenase
  • MMP-10 also known as stromelysin-2
  • MMP-11 also known as stromelysin-3
  • MMP- 12 also known as metalloelastase
  • MMP-13 also known as collagenase-3;
  • MMP-14 also known as membrane-type (“MT") 1-MMP or MT1-MMP
  • MMP-15 also known as MT2-MMP
  • MMP-16 also known as MT3-MMP
  • MMP-17 also known as MT4-MMP
  • MMP-18 and
  • MMPs include MMP-26 (Matrilysin-2).
  • the term "arthritis”, which is synonymous with the phrase “arthritic condition” includes osteoarthritis, rheumatoid arthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, and psoriatic arthritis.
  • An allosteric compound inhibitor of MMP-13 having an anti-arthritic effect is a compound as defined above that inhibits the progress, prevents further progress, or reverses progression, in part or in whole, of any one or more symptoms of any one of the arthritic diseases and disorders listed above.
  • IC 50 means the concentration of a compound, usually expressed as micromolar or nanomolar, required to inhibit an enzyme's catalytic activity by 50%.
  • ED 40 means the concentration of a compound, usually expressed as micromolar or nanomolar, required to treat a disease in about 40% of a patient group.
  • ED 3 0 means the concentration of a compound, usually expressed as micromolar or nanomolar, required to treat a disease in 30% of a patient group.
  • composition means a composition suitable for administration in medical or veterinary use.
  • admixed and the phrase “in admixture” are synonymous and mean in a state of being in a homogeneous or heterogeneous mixture. Preferred is a homogeneous mixture.
  • the phrase "cartilage damage” means a disorder of hyaline cartilage and subchondral bone characterized by hypertrophy of tissues in and around the involved joints, which may or may not be accompanied by deterioration of hyaline cartilage surface.
  • the phrase “treating”, which is related to the terms “treat” and “treated”, means administration of an invention combination as defined above that inhibits the progress, prevents further progress, or reverses progression, in part or in whole, of any one or more symptoms of any one of the diseases and disorders listed above.
  • invention compound means a compound of Formula I, or a pharmaceutically acceptable salt thereof, as fully defined above.
  • nontoxic means the efficacious dose is 10 times or greater than the dose at which a toxic effect is observed in 10% or more of a patient population.
  • celecoxib means the compound named 4-(5-(4-methylphenyl)-
  • Celecoxib is a selective cyclooxygenase-2 ("COX-2") inhibitor currently approved by the FDA for the treatment of osteoarthritis, rheumatoid arthritis, and Polyposis-familial adenomatus.
  • COX-2 selective cyclooxygenase-2
  • Celecoxib is marketed under the tradename "Celebrex”.
  • Celecoxib is currently in clinical trials for the treatment of bladder cancer, chemopreventative- lung cancer, and post-operative pain, and is registered for the treatment of dysmenorrhea.
  • Celecoxib has the structure drawn below:
  • Valdecoxib means the compound named 4-(5-methyl-3-phenyl- 4-isoxazolyl)-benzenesulfonamide.
  • Valdecoxib is a selective COX-2 inhibitor that has been approved by the FDA for treating osteoarthritis, rheumatoid arthritis, dysmenorrhea, and general pain, and is marketed under the tradename "Bextra”.
  • Valdecoxib is in clinical trials for the treatment of migraine.
  • Valdecoxib has the structure drawn below:
  • COX-2 is also known as prostaglandin synthase-2 and prostaglandin PGH 2 synthase.
  • a selective inhibitor of COX-2 means compounds that inhibit COX-2 selectively versus COX-1 such that a ratio of IC50 for a compound with COX-1 divided by a ratio of IC 50 for the compound with COX-2 is greater than, or equal to, 5, where the ratios are determined in one or more assays. All that is required to determine whether a compound is a selective COX-2 inhibitor is to assay a compound in one of a number of well know assays in the art.
  • NSAID is an acronym for the phrase “nonsteroidal anti- inflammatory drug", which means any compound which inhibits cyclooxygenase- 1 ("COX-1") and cyclooxygenase-2.
  • Most NSAIDs fall within one of the following five structural classes: (1) propionic acid derivatives, such as ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen; (2) acetic acid derivatives, such as tolmetin and sulindac; (3) fenamic acid derivatives, such as mefenamic acid and meclofenamic acid; (4) biphenylcarboxylic acid derivatives, such as diflunisal and flufenisal; and (5) oxicams, such as piroxim, peroxicam, sudoxicam, and isoxicam.
  • Other useful NSAIDs include aspirin, acetaminophen, indomethacin, and phenylbutazone. Selective inhibitors of
  • diclonedimetics which is synonymous with the phrases “active components”, “active compounds”, and “active ingredients”, includes celecoxib, or a pharmaceutically acceptable salt thereof, valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric inhibitor of MMP-13, and may further include one or two of the other therapeutic agents described above.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof, or tautomers thereof, include compounds which are invention compounds.
  • An allosteric inhibitor of MMP-13 is any compound of Formula I that binds allosterically into the SI' site of the MMP-13 enzyme, including the SI' channel, and a newly discovered SI" site, without ligating, coordinating, or binding the catalytic zinc of the MMP-13.
  • An invention compound that is an allosteric inhibitor of MMP-13 may be readily identified by one of ordinary skill in the pharmaceutical or medical arts by assaying an alkyne test compound for inhibition of MMP-13 as described below in Biological Methods 1 or 2, and for allosteric inhibition of MMP-13 by assaying the test invention compound for inhibition of MMP-13 in the presence of an inhibitor to the catalytic zinc of MMP-13 as described below in Biological
  • an invention compound having an anti-inflammatory, an analgesic, anti-arthritic, or a cartilage damage inhibiting effect, or any co bination of these effects may be readily identified by one of ordinary skill in the pharmaceutical or medical arts by assaying the invention compound in any number of well known assays for measuring determining the invention compound's effects on cartilage damage, arthritis, inflammation, or pain.
  • assays include in vitro assays that utilize cartilage samples and in vivo assays in whole animals that measure cartilage degradation, inhibition of inflammation, or pain alleviation.
  • an amount of an invention compound or control vehicle may be administered with a cartilage damaging agent to cartilage, and the cartilage damage inhibiting effects in both tests studied by gross examination or histopathologic examination of the cartilage, or by measurement of biological markers of cartilage damage such as, for example, proteoglycan content or hydroxyproline content.
  • an amount of an invention compound or control vehicle may be administered with a cartilage damaging agent to an animal, and the effects of the invention compound being assayed on cartilage in the animal may be evaluated by gross examination or histopathologic examination of the cartilage, by observation of the effects in an acute model on functional limitations of the affected joint that result from cartilage damage, or by measurement of biological markers of cartilage damage such as, for example, proteoglycan content or hydroxyproline content.
  • the amount to be administered in an assay is dependent upon the particular assay employed, but in any event is not higher than the well known maximum amount of a compound that the particular assay can effectively accommodate.
  • invention compounds having pain-alleviating properties may be identified using any one of a number of in vivo animal models of pain.
  • invention compounds having anti-inflammatory properties may be identified using any one of a number of in vivo animal models of inflammation.
  • inflammation models see United States patent number 6, 329,429, which is incorporated herein by reference. -58-
  • invention compounds having anti-arthritic properties may be identified using any one of a number of in vivo animal models of arthritis.
  • arthritis models see also United States patent number 6, 329,429.
  • Other mammalian diseases and disorders which are treatable by administration of an invention combination alone, or contained in a pharmaceutical composition as defined below, include: fever (including rheumatic fever and fever associated with influenza and other viral infections), common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostrate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin's disease; aplastic anemia, skin cancer and familiar adenomatous polyposis),
  • fever including r
  • periarteritis nodosa congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain (including low back and neck pain, headache and toothache), gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursit
  • selectivity of a compound of Formula I, or a pharmaceutically acceptable salt thereof is a multidimensional characteristic that includes the number of other MMP enzymes and TACE over which selectivity for MMP-13 inhibition is present and the degree of selectivity of inhibition of MMP- 13 over another particular MMP or TACE, as measured by, for example, the IC 50 in micromolar concentration of the compound for the inhibition of the other MMP enzyme or TACE divided by the IC 50 in micromolar concentration of the compound for the inhibition of MMP-13.
  • a selective inhibitor of MMP-13 is a compound that is >5X more potent in vitro versus MMP-13 than versus at least one other matrix metalloproteinase enzyme such as, for example, MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, or MMP-14, or versus tumor necrosis factor alpha convertase ("TACE").
  • TACE tumor necrosis factor alpha convertase
  • a preferred aspect of the present invention is novel compounds that are selective inhibitors of MMP-13 versus MMP-1.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, which has an IC 50 with any MMP enzyme that is less than or equal to 50 micromolar.
  • compounds of Formula I, or a pharmaceutically acceptable salt thereof which have an IC 50 with a human full- length MMP-13 (“hMMP-13FL”) or a human MMP-13 catalytic domain (“hMMP-13CD”) that is less than or equal to 50 micromolar.
  • compounds of Formula I, or a pharmaceutically acceptable salt thereof which have an IC 50 with a human full-length MMP-13 (“hMMP-13FL") or a human
  • hMMP-13CD MMP-13 catalytic domain
  • Some of the invention compounds are capable of further forming nontoxic pharmaceutically acceptable salts, including, but not limited to, acid addition and/or base salts.
  • the acid addition salts are formed from basic invention compounds, whereas the base addition salts are formed from acidic invention compounds. All of these forms are within the scope of the compounds useful in the invention.
  • Pharmaceutically acceptable acid addition salts of the basic invention compounds include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
  • inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic s
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like.
  • salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S.M.
  • An acid addition salt of a basic invention compound is prepared by contacting the free base form of the compound with a sufficient amount of a desired acid to produce a nontoxic salt in the conventional manner.
  • the free base form of the compound may be regenerated by contacting the acid addition salt so formed with a base, and isolating the free base form of the compound in the conventional manner.
  • the free base forms of compounds prepared according to a process of the present invention differ from their respective acid addition salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise free base forms of the invention compounds and their respective acid addition salt forms are equivalent for purposes of the present invention.
  • a nontoxic pharmaceutically acceptable base addition salt of an acidic invention compound may be prepared by contacting the free acid form of the compound with a metal cation such as an alkali or alkaline earth metal cation, or an amine, especially an organic amine.
  • a metal cation such as an alkali or alkaline earth metal cation, or an amine, especially an organic amine.
  • suitable metal cations include sodium cation (Na + ), potassium cation (K + ), magnesium cation (Mg2+), calcium cation (Ca2+), and the like.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, supra., 1977).
  • a base addition salt of an acidic invention compound may be prepared by contacting the free acid form of the compound with a sufficient amount of a desired base to produce the salt in the conventional manner.
  • the free acid form of the compound may be regenerated by contacting the salt form so formed with an acid, and isolating the free acid of the compound in the conventional manner.
  • the free acid forms of the invention compounds differ from their respective salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
  • Certain invention compounds can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms, including hydrated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.
  • invention compounds possess one or more chiral centers, and each center may exist in the R or S configuration.
  • An invention compound includes any diastereomeric, enantiomeric, or epimeric form of the compound, as well as mixtures thereof.
  • invention compounds may exist as geometric isomers such as the Seven (E) and sixteen (Z) isomers of 1,2-disubstituted alkenyl groups or cis and trans isomers of disubstituted cyclic groups.
  • An invention compound includes any cis, trans, syn, anti,
  • Certain invention compounds can exist as two or more tautomeric forms.
  • Tautomeric forms of the invention compounds may interchange, for example, via enolization/de-enolization, 1,2-hydride, 1,3-hydride, or 1,4-hydride shifts, and the like.
  • An invention compound includes any tautomeric form of the compound, as well as mixtures thereof.
  • Some compounds of the present invention have alkenyl groups, which may exist as Chrysler or sixteen conformations, in which case all geometric forms thereof, both Cyprus and sixteen, cis and trans, and mixtures thereof, are within the scope of the present invention.
  • Some compounds of the present invention have cycloalkyl groups, which may be substituted at more than one carbon atom, in which case all geometric forms thereof, both cis and trans, and mixtures thereof, are within the scope of the present invention.
  • the invention compounds also include isotopically-labelled compounds, which are identical to those recited above, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, I7 0, 31 P, 32 P, 35 S, 18 F and 36 C1, respectively.
  • Compounds of the present invention and pharmaceutically acceptable salts of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • isotopically labelled compounds of those described above in this invention can generally be prepared by carrying out the procedures incorporated by reference above or disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. All of the above-describe forms of an invention compound are included by the phrase "invention compound", a "compound of Formula I", a "compound of Formula I, or a pharmaceutically acceptable salt thereof, or any named species thereof, unless specifically excluded therefrom.
  • the compounds of the invention are useful in treating a diverse array of diseases.
  • One of ordinary skill in the art will also appreciate that when using the compounds of the invention in the treatment of a specific disease that the compounds of the invention may be combined with various existing therapeutic agents used for that disease.
  • the compounds of the invention may be combined with agents such as TNF- inhibitors such as anti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules (such as Enbrel®), low dose methotrexate, lefunimide, hydroxychloroquine, d- penicillamine, auranofin or parenteral or oral gold.
  • TNF- inhibitors such as anti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules (such as Enbrel®)
  • low dose methotrexate such as anti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules (such as Enbrel®)
  • lefunimide such as hydroxychloroquine
  • d- penicillamine such as Enbrel®
  • the compounds of the invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis.
  • Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents
  • NSAID's such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as etoricoxib and rofecoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc.
  • piroxicam such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen
  • fenamates such as mefenamic acid, indomethacin, sulindac,
  • This invention also relates to a method of or a pharmaceutical composition for treating inflammatory processes and diseases comprising administering a compound of this invention to a mammal, including a human, cat, livestock or dog, wherein said inflammatory processes and diseases are defined as above and said inhibitory compound is used in combination with one or more other therapeutically active agents under the following conditions:
  • inhibitory compound where a joint has become seriously inflamed as well as infected at the same time by bacteria, fungi, protozoa and/or virus, said inhibitory compound is administered in combination with one or more antibiotic, antifungal, antiprotozoal and/or antiviral therapeutic agents;
  • inhibitory compound where a multi-fold treatment of pain and inflammation is desired, said inhibitory compound is administered in combination with inhibitors of other mediators of inflammation, comprising one or more members independently selected from the group consisting essentially of:
  • prostaglandin inhibitors selected from the group consisting of PGD-, PGF- PGI 2 - and PGE-receptor antagonists ;
  • TXA 2 - thromboxane A 2 (TXA 2 -) inhibitors
  • anti-gout agents including colchicine; xanthine oxidase inhibitors including allopurinol; and uricosuric agents selected from probenecid, sulfinpyrazone and benzbromarone;
  • inhibitory compound is administered in combination with one or more members independently selected from the group consisting essentially of:
  • anti-hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, hypertension, myocardial ischemia, angina, congestive heart failure and myocardial infarction, selected from the group consisting of: a. diuretics; b. vasodilators; c. ⁇ -adrenergic receptor antagonists; d. angiotensin-LI converting enzyme inhibitors (ACE-inhibitors), alone or optionally together with neutral endopeptidase inhibitors; e. angiotensin II receptor antagonists; f. renin inhibitors; g. calcium channel blockers; h. sympatholytic agents; i. 2 -adrenergic agonists; j. ⁇ -adrenergic receptor antagonists; and k. HMG-CoA-reductase inhibitors (anti-hypercholesterolemics);
  • antineoplastic agents selected from: a. antimitotic drugs selected from: i. vinca alkaloids selected from: [1] vinblastine and
  • the active ingredient of the present invention may be administered in combination with inhibitors of other mediators of inflammation, comprising one or more members selected from the group consisting essentially of the classes of such inhibitors and examples thereof which include, matrix metalloproteinase inhibitors, aggrecanase inhibitors, TACE inhibitors, leucotriene receptor antagonists, IL-1 processing and release inhibitors, ILra, Hi -receptor antagonists; kinin-Bi - and B 2 -receptor antagonists; prostaglandin inhibitors such as PGD-, PGF- PGI 2 - and PGE-receptor antagonists; thromboxane A (TXA2-) inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene LTC 4 -, LTD 4 /LTE 4 - and LTB 4 - inhibitors; PAF-receptor antagonists; gold in the form of an aurothio group together with various hydrophilic groups; immunosuppressive agents, e.g.,
  • the compounds of the present invention may also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine and antimetabolites such as methotrexate.
  • anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine and antimetabolites such as methotrexate.
  • the compounds of the present invention may also be used in combination with anti-hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, including hypertension, myocardial ischemia including angina, congestive heart failure and myocardial infarction, selected from vasodilators such as hydralazine, ⁇ -adrenergic receptor antagonists such as propranolol, calcium channel blockers such as nifedipine, ⁇ 2 -adrenergic agonists such as clonidine, -adrenergic receptor antagonists such as prazosin and HMG- CoA-reductase inhibitors (anti-hypercholesterolemics) such as lovastatin or atorvastatin.
  • vasodilators such as hydralazine
  • ⁇ -adrenergic receptor antagonists such as propranolol
  • calcium channel blockers such as nifedipine
  • the compounds of the present invention may also be administered in combination with one or more antibiotic, antifungal, antiprotozoal, antiviral or similar therapeutic agents.
  • the compounds of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as L-dopa, requip, mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists and inhibitors of neuronal nitric oxide synthase) and anti- Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.
  • CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as L-dopa, requip, mirapex, MAOB inhibitors such as seleg
  • the compounds of the present invention may also be used in combination with osteoporosis agents such as roloxifene, lasofoxifene, droloxifene or fosomax and immunosuppressant agents such as FK-506 and rapamycin.
  • the present invention also relates to the formulation of a compound of the present invention alone or with one or more other therapeutic agents which are to form the intended combination, including wherein said different drugs have varying half -lives, by creating controlled-release forms of said drugs with different release times which achieves relatively uniform dosing; or, in the case of non-human patients, a medicated feed dosage form in which said drugs used in the combination are present together in admixture in the feed composition.
  • co-administration in which the combination of drugs is achieved by the simultaneous administration of said drugs to be given in combination; including co-administration by means of different dosage forms and routes of administration; the use of combinations in accordance with different but regular and continuous dosing schedules whereby desired plasma levels of said drugs involved are maintained in the patient being treated, even though the individual drugs making up said combination are not being administered to said patient simultaneously.
  • the invention method is useful in human and veterinary medicines for treating mammals suffering from one or more of the above-listed diseases and disorders.
  • All that is required to practice a method of this invention is to administer a compound of Formula I, or a pharmaceutically acceptable salt thereof, in an amount that is therapeutically effective for preventing, inhibiting, or reversing the condition being treated.
  • the invention compound can be administered directly or in a pharmaceutical composition as described below.
  • a therapeutically effective amount, or, simply, effective amount, of an invention compound will generally be from about 1 to about 300 mg/kg of subject body weight of the compound of Formula I, or a pharmaceutically acceptable salt thereof. Typical doses will be from about 10 to about 5000 mg/day for an adult subject of normal weight for each component of the combination. In a clinical setting, regulatory agencies such as, for example, the Food and Drug Administration (“FDA”) in the U.S. may require a particular therapeutically effective amount.
  • FDA Food and Drug Administration
  • the administered dose may fall within the ranges or concentrations recited above, or may vary outside them, ie, either below or above those ranges, depending upon the requirements of the individual subject, the severity of the condition being treated, and the particular therapeutic formulation being employed. Determination of a proper dose for a particular situation is within the skill of the medical or veterinary arts. Generally, treatment may be initiated using smaller dosages of the invention compound that are less than optimum for a particular subject. Thereafter, the dosage can be increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
  • compositions described briefly here and more fully below, of an invention combination may be produced by formulating the invention combination in dosage unit form with a pharmaceutical carrier.
  • dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses.
  • the invention compounds may be formulated separately.
  • suitable pharmaceutical carriers including pharmaceutical diluents
  • suitable pharmaceutical carriers are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations.
  • compositions to be employed in the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts.
  • the compositions can, if desired, also contain other therapeutic agents commonly employed to treat any of the above-listed diseases and disorders.
  • the percentage of the active ingredients of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the foregoing compositions can be varied within wide limits, but for practical purposes it is preferably present in a total concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition.
  • the most satisfactory compositions are those in which a much higher proportion of the active ingredients are present, for example, up to about 95%.
  • Preferred routes of administration of an invention compound are oral or parenteral. However, another route of administration may be preferred depending upon the condition being treated. For exampled, topical administration or administration by injection may be preferred for treating conditions localized to the skin or a joint. Administration by transdermal patch may be preferred where, for example, it is desirable to effect sustained dosing.
  • a useful intravenous (“IV") dose is between 5 and 50 mg
  • a useful oral dosage is between 20 and 800 mg, of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • the dosage is within the dosing range used in treatment of the above-listed diseases, or as would be determined by the needs of the patient as described by the physician.
  • the invention compounds may be administered in any form. Preferably, administration is in unit dosage form.
  • a unit dosage form of the invention compound to be used in this invention may also comprise other compounds useful in the therapy of diseases described above.
  • a further description of pharmaceutical formulations useful for administering the invention compounds and invention combinations is provided below.
  • the active components of the invention combinations may be formulated together or separately and may be administered together or separately.
  • the particular formulation and administration regimens used may be tailored to the particular patient and condition being treated by a practitioner of ordinary skill in the medical or pharmaceutical arts.
  • the advantages of using an invention compound in a method of the instant invention include the nontoxic nature of the compounds at and substantially above therapeutically effective doses, their ease of preparation, the fact that the compounds are well-tolerated, and the ease of topical, IV, or oral administration of the drugs.
  • Another important advantage is that the present invention compounds more effectively target a particular disease that is responsive to inhibition of MMP-13 with fewer undesirable side effects than similar compounds that inhibit MMP-13 that are not invention compounds.
  • the instant invention compounds of Formula I, or a pharmaceutically acceptable salt thereof do not directly, or indirectly via a bridging water molecule, ligate, coordinate to, or bind to the catalytic zinc cation of MMP-13, but instead bind at a different location from where natural substrate binds to MMP-13.
  • the binding requirements of an allosteric MMP-13 binding site are unique to MMP-13, and account for the specificity of the invention compounds for inhibiting MMP-13 over any other MMP enzyme. This binding mode has not been reported in the art.
  • prior art inhibitors of MMP-13 bind to the catalytic zinc cations of other MMP enzymes as well as to the catalytic zinc cation of MMP-13, and are consequently significantly less selective inhibitors of MMP-13 enzyme.
  • the invention compounds which are invention compounds, and pharmaceutically acceptable salts thereof, are thus therapeutically superior to other inhibitors of MMP-13, or even tumor necrosis factor-alpha converting enzyme ("TACE"), because of fewer undesirable side effects from inhibition of the other MMP enzymes or TACE.
  • TACE tumor necrosis factor-alpha converting enzyme
  • virtually all prior art MMP inhibitors tested clinically to date have exhibited an undesirable side effect known as muscoloskeletal syndrome ("MSS").
  • MSS is associated with administering an inhibitor of multiple MMP enzymes or an inhibitor of a particular MMP enzyme such as MMP-1. MSS will be significantly reduced in type and severity by administering the invention compound instead of any prior art MMP-13 inhibitor, or a pharmaceutically acceptable salt thereof.
  • the invention compounds are superior to similar compounds that interact with the catalytic zinc cation of the MMP-13 enzyme as discussed above, even if similar compounds show some selectivity for the MMP- 13.
  • This advantage of the instant compounds will also significantly increase the likelihood that agencies which regulate new drug approvals, such as the United States Food and Drug Administration, will approve the instant compounds versus a competing similar compound that does not allosterically bind to MMP-13 as discussed above even in the unlikely event that the two compounds behaved similarly in clinical trials.
  • agencies which regulate new drug approvals such as the United States Food and Drug Administration
  • These regulatory agencies are increasingly aware that clinical trials, which test drug in limited population groups, do not always uncover safety problems with a drug, and thus all other things being equal, the agencies will favor the drug with the lowest odds of producing undesirable side effects.
  • the disease modifying properties of the invention compounds provide patients suffering from cartilage damage, arthritis, preferably osteoarthritis, inflammation and/or pain with both relief of symptoms and prevention or inhibition of the underlying disease pathology such as cartilage degradation.
  • Any invention compound is readily available, either commercially, or by synthetic methodology, well known to those skilled in the art of organic chemistry. For specific syntheses, see the examples below and the preparations of invention compound outlined in the Schemes below.
  • Preparations of the invention compounds may use starting materials, reagents, solvents, and catalysts that may be purchased from commercial sources or they may be readily prepared by adapting procedures in the references or resources cited above.
  • Commercial sources of starting materials, reagents, solvents, and catalysts useful in preparing invention compounds include, for example, The Aldrich Chemical Company, and other subsidiaries of Sigma- Aldrich Corporation, St. Louis, Missouri, BACHEM, BACHEM A.G.,
  • Syntheses of some invention compounds may utilize starting materials, intermediates, or reaction products that contain a reactive functional group.
  • a reactive functional group may be protected from reacting by a protecting group that renders the reactive functional group substantially inert to the reaction conditions employed.
  • a protecting group is introduced onto a starting material prior to carrying out the reaction step for which a protecting group is needed. Once the protecting group is no longer needed, the protecting group can be removed. It is well within the ordinary skill in the art to introduce protecting groups during a synthesis of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and then later remove them.
  • protecting groups such as the following may be utilized to protect amino, hydroxyl, and other groups: carboxylic acyl groups such as, for example, formyl, acetyl, and trifluoroacetyl; alkoxycarbonyl groups such as, for example, ethoxycarbonyl, tert-butoxycarbonyl (BOC), ⁇ , ⁇ , ⁇ - trichloroethoxycarbonyl (TCEC), and ⁇ -iodoethoxycarbonyl; aralkyl ox ycarbonyl groups such as, for example, benzyloxycarbonyl (CBZ), para- methoxybenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl (FMOC); trialkylsilyl groups such as, for example, trimethylsilyl (TMS) and tert- butyldimethylsilyl (TBDMS); and other groups such as, for example, triphenylmethyl (trityl),
  • Examples of procedures for removal of protecting groups include hydrogenolysis of CBZ groups using, for example, hydrogen gas at 50 psi in the presence of a hydrogenation catalyst such as 10% palladium on carbon, acidolysis of BOC groups using, for example, hydrogen chloride in dichloromethane, trifluoroacetic acid (TFA) in dichloromethane, and the like, reaction of silyl groups with fluoride ions, and reductive cleavage of
  • Q is a carbon-carbon triple bond
  • W 1 is N
  • R 4 , W 2 , W 3 , and W 4 are each CH
  • n is 0.
  • a suspension of 7-bromo-l-hydroxy-3-azaisoquinoline (A) can be alkylated in an aprotic solvent such as dimethylformamide when treated with a common alkylating agent such as an alkyl halide or benzyl halide, generally in the presence of a base such as cesium carbonate, potassium carbonate, or triethylamine.
  • a common alkylating agent such as an alkyl halide or benzyl halide
  • the alkylated isoquinoline (B) can be further reacted with a variety of alkynes using standard coupling conditions known to those skilled in the art, for example, using a catalyst such as Pd(PPh 3 ) 4 or PdCl 2 ((PPh 3 ) 2 , with or without an accompanying ligand, and in the presence of a base, such as triethylamine or diisopropylamine, to give compounds of this invention (C).
  • a catalyst such as Pd(PPh 3 ) 4 or PdCl 2 ((PPh 3 ) 2 , with or without an accompanying ligand
  • a base such as triethylamine or diisopropylamine
  • the invention compounds can be isolated and purified by standard methods such as crystallization from solvents such as alkanes, alkyl esters and ethyl acetate, and chromatography over solid supports such as silica gel, eluting with solvents such as dichloromethane, acetonitrile, tetrahydrofuran, hexanes, ethyl acetate.
  • R 1 and R 2 are as defined above for Formula I.
  • Compounds of Formula I wherein W 1 is N and W 2 to W 4 are each C-R 7 are also known as phthalazinone derivatives. Phthalazinone derivatives may also be prepared according to the procedures referenced below for Figure 1.
  • a bromo-substituted phthalazinone of formula (D) and a carboxylic acid ester of formula (E) may be prepared according to the procedure described in Chem. Pharm. Bull., 1985;33(7):2809-2820.
  • Compounds of formulas (D) and (E) may be used to prepare compounds of Formula HI, which are compounds of Formula I wherein Y is C(O) and Q is a carbon-carbon triple bond, amide, or ester linker.
  • Figure 1 a bromo-substituted phthalazinone of formula (D) and a carboxylic acid ester of formula (E)
  • R 1 and R 2 are as defined above for Formula I.
  • (H) may be used to prepare compounds of Formula IV, V, and VI, respectively, which are compounds of Formula I wherein Y is C(O) and Q is a carbon-carbon triple bond, amide, or ester linker.
  • Figure 2
  • bromo-substituted compounds of formula (I) may be converted, for example, to carboxylic acid esters of formula (J) using conventional carbonylation methods. Alkylation of the compounds of formula (J), followed by hydrolysis will afford the carboxylic acid intermediate of formula (K), which can then be used to make several of the heterocyclic linkers, including compounds of Formula (Vu). Scheme 2b.
  • Step (1) 4-(7-bromo-l-oxo-lH-3-azaisoquinolin-2-ylmethyl)benzoic acid tert- butyl ester
  • a suspension of 7-bromo-l-hydroxy-3-azaisoquinoline (7.02g, 28.2mmol) in dimethylformamide (75mL) is treated with 4-bromomethylbenzoic acid tert- butyl ester (12.5g, 36.7mmol) and cesium carbonate (11.94g, 36.7mmol), then stirred overnight at room temperature.
  • the dimethylformamide is evaporated in vacuo, the residue is diluted with ethyl acetate, washed with IN HCI, the organic portion washed with brine, dried over MgSO and evaporated to dryness.
  • the residue is triturated with hot hexanes/ethyl acetate, cooled to room temperature, and the solid is collected by filtration and dried to give the desired product.
  • Step (2) 4-[l-oxo-7-(3-phenyl-prop-l-ynyl)-lH-3-azaisoquinolin-2- ylmethyljbenzoic acid tert-butyl ester
  • the solid is then dissolved in hot ethyl acetate, evaporated onto silica gel, and purified on a 2.5X10cm silica gel column eluted with hexanes/ethyl acetate 1:1, followed by ethyl acetate. Drying will afford the purified product.
  • the alkylation of 7-bromo-l-hydroxy-5-azaisoquinoline (l.OOg, 4.40mmol) using 4-trifluoromethyl-benzyl bromide (1.60g, 6.69mmol) and cesium carbonate (2.18g, 6.69mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 2:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product.
  • Step (1) 7-bromo-2-(3-fluorobenzyl)-2H-5-azaisoquinolin-l-one
  • Step (2) 2-(3-fluorobenzyl)-7-(3-phenyl-prop-l-ynyl)-2H-5-azaisoquinolin-l-one
  • Step (1) 3-[l-Oxo-7-(3-phenyl-prop-l-ynyl)-lH-6-azaisoquinolin-2-ylmethyl]benzonitrile
  • Step (1) 3-(7-bromo-l-oxo-lH-6-azaisoquinolin-2-ylmethyl)benzonitrile
  • the alkylation of 7-bromo-l-hydroxy-6-azaisoquinoline (l.OOg, 4.40mmol) using 3-cyanobenzyl bromide (1.3 lg, 6.69mmol) and cesium carbonate (2.18g, 6.69mmol) in dimethylformamide is carried out as previously described in Example 1, Step (1).
  • Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product.
  • Step (2) 3- [ l-oxo-7-(3-phenyl-prop- 1 -ynyl)- 1 H-6-azaisoquinolin-2- ylmethyljbenzonitrile
  • Step (1) 4-(7-bromo-l-oxo-lH-6-azaisoquinolin-2-ylmethyl)benzenesulfonamide
  • the alkylation of 7-bromo-l-hydroxy-6-azaisoquinoline (l.OOg, 4.40mmol) using 4-bromomethyl-benzene sulfonamide (1.67g, 6.69mmol) and cesium carbonate (2.18g, 6.69mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product.
  • Step (2) 4- [ 1 -oxo-7-(3-phenyl-prop- 1 -ynyl)- lH-6-azaisoquinolin-2- ylmethyljbenzenesulfonamide
  • Step (1) 4-(7-bromo-l-oxo-lH-8-azaisoquinolin-2-ylmethyl)benzoic acid methyl ester
  • Step (2) 4- [ 1 -oxo-7-(3-phenyl-prop- 1 -ynyl)- lH-8-azaisoquinolin-2- ylmethyl]benzoic acid methyl ester
  • Step (1) 3-(7-bromo-l-oxo-lH-8-azaisoquinolin-2-ylmethyl)benzoic acid methyl ester
  • the alkylation of 7-bromo-l-hydroxy-8-azaisoquinoline (l.OOg, 4.46mmol) using methyl 3-(bromomethyl)benzoate (1.53g, 6.69mmol) and cesium carbonate (2.18g, 6.69mmol) in dimethyl -formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product.
  • Step (2) 3-[l-oxo-7-(3-phenyl-prop-l-ynyl)-lH-8-azaisoquinolin-2- ylmethyljbenzoic acid methyl ester
  • Step (2) 2-(4-fluorobenzyl)-7-3-phenylprop-l-ynyl-2H-3,5-diazaisoquinolin-l- one
  • the resulting red oil is purified on the preparatory HPLC using 80:20 acetonitrile/water (0.1%TFA), evaporated to dryness, dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over MgSO 4 and evaporated to dryness. Drying will afford the desired product.
  • Step (1) 7-bromo-2-(3-trifluoromethylbenzyl)-2H-3,6-diazaisoquinolin-l-one The alkylation of 7-bromo-l-hydroxy-3,6-diazaisoquinoline (l.OOg,
  • Step (2) 7-(3-phenylprop-l-ynyl)-2-(3-trifluoromethylbenzyl)-2H-3,6- diazaisoquinolin-1-one
  • the resulting red oil is purified on the preparatory HPLC using 80:20 acetonitrile/water (0.1%TFA), washed with saturated aqueous sodium bicarbonate solution, dried over MgSO 4 and evaporated to dryness. Drying will afford the desired product.
  • Step (1) 7-bromo-2-(3-chlorobenzyl)-2H-3,8-diazaisoquinolin-l-one
  • Step 2) 2-(3-chlorobenzyl)-7-(3-phenylprop-l-ynyl)-2H-3,8-diazaisoquinolin-l- one
  • Step (2) 2-(3,4-difluorobenzyl)-7-(3-phenyl ⁇ rop-l-ynyl)-2H-5,8- diazaisoquinolin-1-one
  • Example 1 Step (2).
  • the resulting red oil is evaporated onto silica gel and purified on a 3.5X20cm silica gel column eluted with hexanes/ethyl acetate 3:1.
  • the resulting red solid is triturated with ethyl ether and dried. This will afford the desired product.
  • the alkylation of 7-bromo-l-hydroxy-3-azaisoquinoline (1.30g,
  • Example 13A is treated with trifluoroacetic acid (6mL) and stirred at room temperature for 30 minutes. The reaction mixture is evaporated to dryness, triturated with ethyl acetate, the solid is collected by filtration, washed with water, washed with ethyl acetate, and dried under house vacuum. This will afford the desired product.
  • EXAMPLE 14A 4- [ 1 -Oxo-7-(3- [ 1 ,2,3] triazol- 1 -ylprop- 1 -ynyl)- lH-6-azaisoquinolin-2- ylmethyljbenzoic acid tert-butyl ester
  • silica gel mesh is purified on a 3.5X18cm silica gel column eluted with hexanes/ethyl acetate 1:1, methylene chloride/THF 7:1, then methylene chloride/THF 4:1. Evaporation and drying will afford the desired product.
  • silica gel mesh is purified on a 3.5X18cm silica gel column eluted with hexanes/ethyl acetate 1:1, methylene chloride/THF 7:1, then methylene chloride/THF 4:1. Evaporation and drying will afford the desired product.
  • Illustrative examples of the coupling reagents and catalysts include palladium tetrakis(triphenylphosphine) or palladium(II) acetate as catalyst, a tertiary organic amine base such as triethylamine or diisopropylethylamine, a suitable solvent such as dimethylformamide (“DMF”) or tetrahydrofuran (“THF”), and optionally a co-catalyst such as copper(I)iodide, at a suitable temperature such as from 0°C to 100°C, for a suitable time such as from 30 minutes to 2 days, and under an inert atmosphere such as an atmosphere of nitrogen or argon gas.
  • bromo or iodo intermediates described above may be converted by conventional means to the corresponding carboxylic acid of formula and the carboxylic acid converted by conventional means to compounds of Formula I wherein Q is OC(O), CH(R 6 )C(O), OC(NR 6 ), CH(R 6 )C(NR 6 ), N(R 6 )C(O), N(R 6 )C(S), N(R 6 )C(NR 6 ), SC(O), CH(R 6 )C(S), or SC(NR 6 ).
  • Illustrative examples include coupling of the carboxylic acid with an amine to provide a compound of Formula I wherein Q is N(R )C(O), and optionally sulfurating the resulting amide with, for example P 2 S 5 to provide a compound of Formula I wherein Q is N(R 6 )C(S).
  • the carboxylic acid may be coupled with an alcohol to provide a compound of Formula I wherein Q is OC(O).
  • the carboxylic acid may be reduced to the corresponding hydroxymethyl compound of formula
  • the hydroxymethyl compound may be oxidized to the corresponding aldehyde of formula
  • the oxime may be chlorinated, and the chlorooxime cyclized with an olefin or alkyne to give a compound of Formula I wherein Q is a 5-membered heteroarylene.
  • the aldehyde may be prepared from the corresponding carboxylic acid by coupling the carboxylic acid with N,O-dimethylhydroxylamine and reducing the resulting dimethylhydroxamide with a suitable hydride reducing agent such as sodium borohydride or lithium aluminum hydride.
  • a suitable hydride reducing agent such as sodium borohydride or lithium aluminum hydride.
  • the above-described carboxylic acid intermediate may be converted by conventional means to the corresponding methyl ketone of formula
  • methyl ketone may be. halogenated on methyl and coupled with various amines, alcohols, or other halogenated compounds to give a compound of Formula I wherein Q is CH(R 6 )C(O).
  • carboxylic acid intermediate or bromo- or iodo-intermediates may be converted by conventional means to the co ⁇ esponding nitrile of formula
  • compounds of Formula I wherein Q is a lactam diradical may be prepared by conventional means by cyclizing the co ⁇ esponding gamma- amino acids.
  • the compounds of Formula I can be evaluated in standard assays for their ability to inhibit the catalytic activity of MMP enzymes.
  • the assays used to evaluate the MMP biological activity of the invention compounds are well-known and routinely used by those skilled in the study of MMP inhibitors and their use to treat clinical conditions.
  • compounds of Formula I may be readily identified by assaying a test compound for inhibition of MMP-13 according to Biological Methods 1 or 2, and further assaying the test compound for allosteric inhibition of MMP-13 according to Biological Methods 3 or 4, as described below.
  • the compounds of Formula I as illustrated by the compounds of Examples 1, 2-12, 13A, 13, 14A, 14, 15A, and 15 will be shown to be potent inhibitors of MMP-13 catalytic domain. Potencies, as measured by IC 50 's, with
  • MMP-13 catalytic domain for the invention compounds will typically range from about 0.001 ⁇ M to about 30 ⁇ M.
  • Invention compounds can be further screened with full-length MMP-2, full-length MMP-7, full-length MMP-9, and MMP-14 catalytic domain to determine selectivity of the inhibitors with MMP-13 versus the other MMP enzymes also.
  • Selectivities of the invention compounds for MMP-13 catalytic domain versus another MMP enzyme (full-length or catalytic domain), as determined by dividing the I o for the inhibitor with a comparator MMP enzyme by the IC 50 of the inhibitor with MMP-13 catalytic domain are expected to range from 5 to 50,000 fold.
  • the compounds of Formula I may be evaluated in standard assays for their ability to inhibit the catalytic activity of various MMP enzymes.
  • the assays used to evaluate the MMP biological activity of the invention compounds are well-known and routinely used by those skilled in the study of MMP inhibitors and their use to treat clinical conditions.
  • the assays measure the amount by which a test compound reduces the hydrolysis of a thiopeptolide substrate catalyzed by a matrix metalloproteinase enzyme.
  • Such assays are described in detail by Ye et al., in Biochemistry, 1992;31(45):11231-11235, which is incorporated herein by reference.
  • One such assay is described below in Biological Method 1.
  • MMP-13CD matrix metalloproteinase- 13 catalytic domain
  • Thiopeptolide substrates show virtually no decomposition or hydrolysis at or below neutral pH in the absence of a matrix metalloproteinase enzyme.
  • a typical thiopeptolide substrate commonly utilized for assays is Ac-Pro-Leu-Gly- thioester-Leu-Leu-GIy-OEt.
  • a 100 ⁇ L assay mixture will contain 50 mM of N-2- hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer ("HEPES,” pH 7.0), 10 mM CaCl2, 100 ⁇ M thiopeptolide substrate, and 1 mM 5,5'-dithio-bis-(2-nitro- benzoic acid) (DTNB).
  • HEPES N-2- hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer
  • CaCl2 100 ⁇ M thiopeptolide substrate
  • DTNB 5,5'-dithio-bis-(2-
  • the thiopeptolide substrate concentration may be varied, for example from 10 to 800 ⁇ M to obtain K m and K ca t values.
  • the change in absorbance at 405 nm is monitored on a Thermo Max microplate reader (molecular Devices, Menlo Park, CA) at room temperature (22°C).
  • the calculation of the amount of hydrolysis of the thiopeptolide substrate is based on
  • E 412 13600 M_1 cm_1 for the DTNB-derived product 3-carboxy- 4-nitrothiophenoxide.
  • Assays are carried out with and without matrix metalloproteinase inhibitor compounds, and the amount of hydrolysis is compared for a determination of inhibitory activity of the test compounds.
  • Test compounds were evaluated at various concentrations in order to determine their respective IC50 values, the micromolar concentration of compound required to cause a 50% inhibition of catalytic activity of the respective enzyme.
  • MMP-13 50 mM N-morpholinoethane sulfonate ("MES") at pH 6.0 rather than the HEPES buffer at pH 7.0 described above.
  • MES N-morpholinoethane sulfonate
  • the test described above for the inhibition of MMP-13 may also be adapted and used to determine the ability of the compounds of Formula I to inhibit the matrix metalloproteases MMP-1, MMP-2, MMP-3, MMP-7, MMP-9,
  • BIOLOGICAL METHOD 2 Some representative compounds of Formula I have been evaluated for their ability to inhibit MMP-13. Inhibitor activity versus other MMPs with the compounds may be determined using, for example, MMP-1FL, which refers to full length interstitial collagenase; MMP-2FL, which refers to full length Gelatinase A; MMP-3CD, which refers to the catalytic domain of stromelysin;
  • MMP-7FL which refers to full length matrilysin
  • MMP-9FL which refers to full length Gelatinase B
  • MMP- 13 CD which refers to the catalytic domain of collagenase 3
  • MMP-14CD which refers to the catalytic domain of MMP- 14.
  • Test compounds can be evaluated at various concentrations in order to determine their respective IC50 values, the micromolar concentration of compound required to cause a 50% inhibition of the hydrolytic activity of the respective enzyme.
  • the compounds of Formula I are potent inhibitors of MMP enzymes, and are especially useful due to their selective inhibition of MMP-13. Because of this potent and selective inhibitory activity, the compounds are especially useful to treat diseases mediated by the MMP enzymes.
  • Allosteric inhibitors of MMP-13 which are compounds of Formula I may be readily identified by assaying a test compound for inhibition of MMP-13 according to the methods described below in Biological Methods 3 and 4.
  • 10X assay buffer 500 mM HEPES buffer (pH 7.0) plus 100 mM CaCl 2
  • lO mM FPl substrate (Mca)-Pro-Leu-Gly-Leu-(Dnp)-Dpa-Ala-Arg-NH2
  • Enzyme dilution buffer 50 mM HEPES buffer (pH 7.0), 10 mM CaCl2, and
  • Fluorimeter F max Fluorescence Microplate Reader & SOFTMAX PRO
  • Protocol menu excitation: 320 nm emission: 405 nm run time: 15 min interval: 29 sec RFU min: -10 RFU max: 200 v max points: 32/32 D. Compared % of control activity and/or IC50 w tn inhibitor test compound
  • Reactions (100 ⁇ L) contain 0.05 M Hepes buffer (pH 7), 0.01 M calcium chloride, 0.005% polyoxyethylene (23) lauryl ether ("Brij 35"), 0 or 15 mM acetohydroxamic acid, 10 ⁇ M FPl, and 0.1 mM to 0.5 nM inhibitor in DMSO (2% final).
  • the initial velocity of FPl hydrolysis is determined by monitoring the increase in fluorescence at 405 nm (upon excitation at 320 nm) continuously for up to 30 minutes on a microplate reader at room temperature.
  • an endpoint read can also be used to determine reaction velocity provided the initial fluorescence of the solution, as recorded before addition of enzyme, is subtracted from the final fluorescence of the reaction mixture.
  • the inhibitor is assayed at different concentration values, such as, for example, 100 ⁇ M, 10 ⁇ M, 1 ⁇ M, 100 nM, 10 nM, and 1 nM. Then the inhibitor concentration is plotted on the X-axis against the percentage of control activity observed for inhibited experiments versus uninhibited experiments (i.e., (velocity with inhibitor) divided by (velocity without inhibitor) x 100) on the Y-axis to determine IC50 values.
  • Results may be expressed as an IC50 Ratio (+/-) ratio, which means a ratio of the IC50 of the inhibitor with MMP-13 and an inhibitor to the catalytic zinc of MMP-13, divided by the IC50 of the inhibitor with MMP-13 without the inhibitor to the catalytic zinc of MMP-13.
  • Compounds of Formula I which are allosteric inhibitors of MMP-13 are expected to have an IC50 Ratio (+/-) ratio of less than I, and are expected to be synergistic with the inhibitor to the catalytic zinc of MMP- 13 such as, for example, AcNHOH.
  • Compounds of Formula I which are not allosteric inhibitors of MMP-13 will be inactive in the assay or will have an IC50
  • Ratio (+/-) of greater than 1 unless otherwise indicated. Results can be confirmed by kinetics experiments which are well known in the biochemical art.
  • MMP-13CD matrix metalloproteinase- 13 catalytic domain
  • Formula I or a pharmaceutically acceptable salt thereof, would be useful for preventing, treating, and inhibiting cartilage damage, and thus for treating osteoarthritis, for example. Examples of such animal models are described below in Biological Methods 5 and 6.
  • BIOLOGICAL METHOD 5 Monosodium Iodoacetate-induced Osteoarthritis in Rat Model of Cartilage Damage ("MIA Rat"):
  • MIA Rat Rat Model of Cartilage Damage
  • Associated with the histologic changes is a concentration-dependent degradation of joint cartilage, as evidenced by affects on hind-paw weight distribution of the limb containing the affected joint, the presence of increased amounts of proteoglycan or hydroxyproline in the joint upon biochemical analysis, or histopathological analysis of the osteoarthritic lesions.
  • the hind-paw weight differential between the right arthritic joint and the left healthy joint of male Wistar rats (150 g) are determined with an incapacitance tester, model 2KG (Linton Instrumentation, Norfolk, United Kingdom).
  • the incapacitance tester has a chamber on top with an outwardly sloping front wall that supports a rat's front limbs, and two weight sensing pads, one for each hind paw, that facilitates this determination.
  • the rats are anesthetized with isofluorine, and the right, hind leg knee joint is injected with 1.0 mg of mono-iodoacetate ("MIA”) through the infrapatellar ligament.
  • MIA mono-iodoacetate
  • the rats are further administered either an invention compound or vehicle (in the instant case, water) daily for 14 days or 28 days.
  • the invention compound is typically administered at a dose of 30 mg per kilogram of rat per day (30 mg/kg/day), but the invention compound may be administered at other doses such as, for example,
  • the animals administered vehicle alone place greater weight on their unaffected left hind paw than on their right hind paw, while animals administered an invention compound show a more normal (i.e., more like a healthy animal) weight distribution between their hind paws.
  • This change in weight distribution was proportional to the degree of joint cartilage damage.
  • Percent inhibition of a change in hind paw joint function is calculated as the percent change in hind-paw weight distribution for treated animals versus control animals. For example, for a two week study,
  • ⁇ Wc is the hind-paw weight differential between the healthy left limb and the arthritic limb of the control animal administered vehicle alone, as measured on Day 14;
  • ⁇ W G is the hind-paw weight differential between the healthy left limb and the arthritic limb of the animal administered an invention compound, as measured on Day 14.
  • the amounts of free proteoglycan in both the osteoarthiitic right knee joint and the contralateral left knee joint may be determined by biochemical analysis.
  • the amount of free proteoglycan in the contralateral left knee joint provides a baseline value for the amount of free proteoglycan in a healthy joint.
  • the amount of proteoglycan in the osteoarthritic right knee joint in animals administered an invention compound, and the amount of proteoglycan in the osteoarthritic right knee joint in animals administered vehicle alone, are independently compared to the amount of proteoglycan in the contralateral left knee joint.
  • the amounts of proteoglycan lost in the osteoarthritic right knee joints are expressed as percent loss of proteoglycan compared to the contralateral left knee joint control.
  • the percent inhibition of proteoglycan loss may be calculated as ⁇ [(proteoglycan loss from joint (%) with vehicle) - (proteoglycan loss from joint with an invention compound)] ⁇ (proteoglycan loss from joint (%) with vehicle) ⁇ x 100.
  • IJFL Inhibition of Joint Function Limitation
  • SDCES Joint Function Limitation
  • SIJWHLE SJJWHLE means Significant Increase in Joints Without Hind Limb Erosion
  • the proportion of subjects without hind limb erosions may be analyzed via an Exact Sequential Cochran-Armitage Trend test (SAS ® Institute, 1999).
  • SAS Exact Sequential Cochran-Armitage Trend test
  • Cochran-Armitage Trend test is employed when one wishes to determine whether the proportion of positive or "Yes" responders increases or decreases with increasing levels of treatment. For the particular study, it is expected that the number of animals without joint erosions increased with increasing dose.
  • Rabbits are given either vehicle (water) or an invention compound dosed three times per day with 30-mg/kg/dose or 10-mg/kg/dose.
  • the invention compound may be administered at other doses such as, for example, 3 times 20 mg/kg/day or 3 times 60 mg/kg/day according to the requirements of the invention compound being studied.
  • the rabbits are euthanized 8 weeks after surgery and the proximal end of the tibia and the distal end of the femur are removed from each animal. Macroscopic Grading
  • the cartilage changes on the femoral condyles and tibial plateaus are graded separately under a dissecting microscope (Stereozoom, Bausch & Lomb, Rochester, NY).
  • the surface area changes are measured and expressed in mm ⁇ . Representative specimens may also be used for histologic grading (see below).
  • Histologic evaluation is performed on sagittal sections of cartilage from the lesional areas of the femoral condyle and tibial plateau. Serial sections (5 um) are prepared and stained with safranin-O. The severity of OA lesions is graded on a scale of 0 - 14 by two independent observers using the histologic-histochemical scale of Mankin et al. This scale evaluates the severity of OA lesions based on the loss of safranin-O staining (scale 0 - 4), cellular changes (scale 0 - 3), invasion of tidemark by blood vessels (scale 0 - 1) and structural changes (scale 0 - 6). On this latter scale, 0 indicates normal cartilage structure and 6 indicates erosion of the cartilage down to the subchondral bone. The scoring system is based on the most severe histologic changes in the multiple sections.
  • Representative specimens of synovial membrane from the medial and lateral knee compartments are dissected from underlying tissues. The specimens are fixed, embedded, and sectioned (5 um) as above, and stained with hematoxylin-eosin. For each compartment, two synovial membrane specimens are examined for scoring purposes and the highest score from each compartment is retained. The average score is calculated and considered as a unit for the whole knee.
  • synovitis is graded on a scale of 0 to 10 by two independent observers, adding the scores of 3 histologic criteria: synovial lining cell hyperplasia (scale 0 - 2); villous hyperplasia (scale 0 - 3); and degree of cellular infiltration by mononuelear and polymorphonuclear cells (scale 0 - 5): 0 indicates normal structure.
  • an invention compound is effective for the inhibition of cartilage damage and inflammation and/or alleviating pain, and thus useful for the treatment of osteoarthritis or rheumatoid arthritis in human, and other mammalian disorders.
  • Such a treatment offers a distinct advantage over existing treatments that only modify pain or inflammation or and other secondary symptoms.
  • the effectiveness of an invention compound in this model would indicate that the invention compound will have clinically useful effects in preventing and/or treating cartilage damage, pain and/or inflammation.
  • Administration according to the invention method of an invention compound to a mammal to treat the diseases listed above is preferably, although not necessarily, accomplished by administering the compound, or a salt thereof, in a pharmaceutical dosage form.
  • the compounds of Formula I, or a pharmaceutically acceptable salt thereof can be prepared and administered according to the invention method in a wide variety of oral and parenteral pharmaceutical dosage forms.
  • the compounds of Formula I, or a pharmaceutically acceptable salt thereof can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of Formula I, or a pharmaceutically acceptable salt thereof can be administered by inhalation, for example, intranasally.
  • the compounds of Formula I, or a pharmaceutically acceptable salt thereof can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component an invention compound.
  • the invention compounds generally are present in a concentration of about 5% to about 95% by weight of the formulation.
  • pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations are preferred. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component. Powders suitable for intravenous administration or administration by injection may be lyophilized.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from about 5% to about 70%, total, of the active component.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation” is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it.
  • Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
  • liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing an appropriate quantity of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 0.01 to 1000 mg, preferably 1 to 500 mg according to the particular application and the potency of the active components.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds of Formula I, or a pharmaceutically acceptable salt thereof are administered at a dose that is effective for treating at least one symptom of the disease or disorder being treated.
  • the initial dosage of about 1 mg/kg to about 100 mg kg daily of the active component will be effective.
  • a daily dose range of about 25 mg/kg to about 75 mg/kg of the active component is prefe ⁇ ed.
  • a preferred composition for dogs comprises an ingestible liquid peroral dosage form selected from the group consisting of a solution, suspension, emulsion, inverse emulsion, elixir, extract, tincture and concentrate, optionally to be added to the drinking water of the dog being treated.
  • liquid dosage forms when formulated in accordance with methods well known in the art, can either be administered directly to the dog being treated, or may be added to the drinking water of the dog being treated.
  • the concentrate liquid form is formulated to be added first to a given amount of water, from which an aliquot amount may be withdrawn for administration directly to the dog or addition to the drinking water of the dog.
  • a preferred composition provides delayed-, sustained- and/or controlled- release of an invention compound.
  • Such prefe ⁇ ed compositions include all such dosage forms which produce > 40% inhibition of cartilage degradation, and result in a plasma concentration of the active component of at least 3 fold the active component's ED 40 for at least 2 hours; preferably for at least 4 hours; preferably for at least 8 hours; more preferably for at least 12 hours; more preferably still for at least 16 hours; even more preferably still for at least 20 hours; and most preferably for at least 24 hours.
  • there is included within the above- described dosage forms those which produce > 40% inhibition of cartilage degradation, and result in a plasma concentration of the active component of at least 5 fold the active component's ED 40 for at least 2 hours, preferably for at least
  • ED 0 for at least 2 hours, preferably for at least 4 hours, preferably for at least 8 hours, more preferably for at least 12 hours, still more preferably for at least 20 hours and most preferably for at least 24 hours.
  • Formulation Examples 1 to 8 illustrate the invention pharmaceutical compositions.
  • the formulations comprise the invention compound and a pharmaceutically acceptable carrier, diluent, or excipient, they contain a cartilage damage treating effective amount or a therapeutically effective amount such as, for example, an anti-osteoarthritic effective amount of the invention compound.
  • a pharmaceutically acceptable carrier, diluent, or excipient they contain a cartilage damage treating effective amount or a therapeutically effective amount such as, for example, an anti-osteoarthritic effective amount of the invention compound.
  • the examples are representative only, and are not to be construed as limiting the invention in any respect.
  • the invention compound, lactose, and cornstarch (for mix) are blended to uniformity.
  • the cornstarch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste.
  • the paste is used to granulate the mixed powders.
  • the wet granules are passed through a No. 8 hand screen and dried at 80°C.
  • the dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet.
  • Such tablets can be administered to a human from one to four times a day for inhibiting cartilage damage or treating osteoarthritis.
  • the pH of a solution of 500 g of an invention compound and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 L of double-distilled water using 2 M hydrochloric acid.
  • the solution is sterile filtered, and the filtrate is filled into injection vials, lyophilized under sterile conditions, and aseptically sealed. Each injection vial contains 25 mg of the invention compound.
  • Each suppository contains 25 mg of the invention compound.
  • a solution of 2.5 kg of an invention compound is dissolved in 60 L of double-distilled water.
  • the solution is sterile filtered, and the filtrate is filled into ampoules.
  • the ampoules are lyophilized under sterile conditions and aseptically sealed.
  • Each ampoule contains 25 mg of the invention compound.
  • Formulation Examples 9 to 16 illustrate the invention pharmaceutical compositions containing an invention combination in a single formulation with a pharmaceutically acceptable carrier, diluent, or excipient.
  • the examples are representative only, and are not to be construed as limiting the invention in any respect.
  • the invention compound or COX-2 inhibitor, lactose, and cornstarch (for mix) are blended to uniformity.
  • the cornstarch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste.
  • the paste is used to granulate the mixed powders.
  • the wet granules are passed through a No. 8 hand screen and dried at 80°C.
  • the dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet.
  • Such tablets can be administered to a human from one to four times a day for treatment of one of the above-listed diseases.
  • the tablets of Formulation Example 9 are coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth, and colorant.
  • FORMULATION EXAMPLE 11 Injection vials: The pH of a solution of 250 g of a COX-2 inhibitor, 500 g of an invention compound, and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 L of double-distilled water using 2 M hydrochloric acid. The solution is sterile filtered, and the filtrate is filled into injection vials, lyophilized under sterile conditions, and aseptically sealed. Each injection vial contains 12.5 mg of COX-2 inhibitor and 25 mg of the invention compound.
  • a mixture of 50 g of a COX-2 inhibitor, 25 g of an invention compound, 100 g of soya lecithin, and 1400 g of cocoa butter is fused, poured into molds, and allowed to cool.
  • Each suppository contains 50 mg of the COX-2 inhibitor and
  • a solution is prepared from 0.5 g of a COX-2 inhibitor, 1 g of an invention compound, 9.38 g of NaH 2 P ⁇ 4-12H2 ⁇ , 28.48 g of Na 2 HP ⁇ 4-12H2 ⁇ , and 0.1 g benzalkonium chloride in 940 mL of double-distilled water.
  • the pH of the solution is adjusted to pH 6.8 using 2 M hydrochloric acid.
  • the solution is diluted to 1.0 L with double-distilled water, and sterilized by irradiation.
  • a 25 mL volume of the solution contains 12.5 mg of the COX-2 inhibitor and 25 mg of the invention compound.
  • Ointment 100 mg of a COX-2 inhibitor, 500 mg of an invention compound is mixed with 99.4 g of petroleum jelly under aseptic conditions. A 5 g portion of the ointment contains 5 mg of the COX-2 inhibitor and 25 mg of the invention compound.
  • a solution of 2.5 kg of a COX-2 inhibitor and 2.5 kg of an invention compound is dissolved in 60 L of double-distilled water.
  • the solution is sterile filtered, and the filtrate is filled into ampoules.
  • the ampoules are lyophilized under sterile conditions and aseptically sealed.
  • Each ampoule contains 25 mg each of the COX-2 inhibitor and the invention compound.
  • COX-2 inhibitor and an invention compound can each be formulated independently in any form such as, for example, those of any one Formulation Examples 1 to 16, and administered to a patient either simultaneously or at different times.
  • An invention compound, lactose, and cornstarch (for mix) are blended to uniformity.
  • the cornstarch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste.
  • the paste is used to granulate the mixed powders.
  • the wet granules are passed through a No. 8 hand screen and dried at 80°C.
  • the dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet.
  • Such tablets containing the invention compound can be administered to a human from one to four times a day for treatment of the above-listed diseases, and the injection solutions containing the COX-2 inhibitor can be administered to a human 1 or 2 times per day, wherein the administration by injection is optionally simultaneous with administration of the tablets or at different times, for the treatment of one of the above-listed diseases.
  • the tablets of Formulation Example 17 are coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth, and colorant.
  • Capsules containing valdecoxib or celecoxib are coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth, and colorant.
  • Such coated tablets containing the invention compound can be administered to a human from one to four times a day for treatment of the above- listed diseases, and the capsules containing the COX-2 inhibitor can be administered to a human 1 or 2 times per day, wherein the administration of the capsules is optionally simultaneous with administration of the tablets or at different times, for the treatment of one of the above-listed diseases.
  • invention methods comprising administering an invention combination to a mammal to treat diseases or disorders listed above may be used to treat different diseases simultaneously.
  • administration of a COX-2 inhibitor in accordance with the invention combination may be carried out as described above to treat inflammation, arthritic pain, pain associated with menstrual cramping, and migraines, while an invention compound may be administered to treat OA or inhibit cartilage damage.
  • the invention methods comprising administering an invention compound offer a distinct advantage over existing treatments for diseases such as OA that comprise cartilage damage, wherein the existing treatments modify pain or secondary symptoms, but do not show a disease modifying effect.

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  • Orthopedic Medicine & Surgery (AREA)
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Abstract

L'invention concerne des composés représentés par la formule (I), dans laquelle R1, Q, Y, R2, R3, R4, R5 et n sont tels que définis dans la description, ou un sel pharmaceutiquement acceptable de ces composés ; des compositions pharmaceutiques comprenant un composé de formule (I), telle que définie dans la description, ou un sel pharmaceutiquement acceptable de ce composé, avec un support, un vecteur ou un excipient pharmaceutiquement acceptable ; des méthodes d'inhibition d'une enzyme MMP-13 chez un animal, consistant à administrer à cet animal un composé de formule (I), ou un sel pharmaceutiquement acceptable de ce composé ; des méthodes de traitement d'une maladie médiée par une enzyme MMP-13 chez un patient, consistant à administrer à ce patient un composé de formule (I), ou un sel pharmaceutiquement acceptable de ce composé, seul ou dans une composition pharmaceutique ; des méthodes de traitement de maladies telles que des cardiopathies, la sclérose en plaques, l'ostéoarthrite et la polyarthrite rhumatoïde, l'arthrite autre que l'ostéoarthrite et la polyarthrite rhumatoïde, une insuffisance cardiaque, une maladie intestinale inflammatoire, une défaillance cardiaque, une dégénérescence maculaire liée à l'âge, la broncho-pneumopathie chronique obstructive, l'asthme, des maladies parodontales, le psoriasis, l'athérosclérose et l'ostéoporose chez un patient, consistant à administrer à ce patient un composé de formule (I), ou un sel pharmaceutiquement acceptable de ce composé, seul ou dans une composition pharmaceutique ; ainsi que des combinaisons comprenant un composé de formule (I), ou un sel pharmaceutiquement acceptable de ce composé, associé à un autre composant pharmaceutiquement actif, tel que défini dans la description.
PCT/IB2003/003485 2002-08-13 2003-08-04 Derives d'azaisoquinoline utilises comme inhibiteurs de metalloproteases matricielles WO2004014866A1 (fr)

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JP2004527200A JP2006504665A (ja) 2002-08-13 2003-08-04 マトリックスメタロプロテイナーゼ阻害剤としてのアザイソキノリン誘導体
EP03784388A EP1539709A1 (fr) 2002-08-13 2003-08-04 Derives d'azaisoquinoline utilises comme inhibiteurs de metalloproteases matricielles
AU2003249531A AU2003249531A1 (en) 2002-08-13 2003-08-04 Azaisoquinoline derivatives as matrix metalloproteinase inhibitors
CA002495293A CA2495293A1 (fr) 2002-08-13 2003-08-04 Derives d'azaisoquinoline utilises comme inhibiteurs de metalloproteases matricielles
BR0313724-4A BR0313724A (pt) 2002-08-13 2003-08-04 Derivados de azaisoquinolina como inibidores de metaloproteinase de matriz
MXPA05001786A MXPA05001786A (es) 2002-08-13 2003-08-04 Derivados de azaisoquinolina como inhibidores de la metaloproteinasa de matriz.

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US11919908B2 (en) 2020-12-21 2024-03-05 Incyte Corporation Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors
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WO2005087767A1 (fr) * 2004-03-09 2005-09-22 Merck & Co., Inc. Inhibiteurs de vih-integrase
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WO2012052451A1 (fr) 2010-10-18 2012-04-26 Merz Pharma Gmbh & Co. Kgaa Modulateurs des récepteurs métabotropes au glutamate
US9682998B2 (en) 2011-05-10 2017-06-20 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9403782B2 (en) 2011-05-10 2016-08-02 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
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US9695192B2 (en) 2011-07-01 2017-07-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9598435B2 (en) 2011-07-01 2017-03-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US10005739B2 (en) 2013-10-23 2018-06-26 Chugai Seiyaku Kabushiki Kaisha Quinazolinone and isoquinolinone derivative
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
US11780840B2 (en) 2020-07-02 2023-10-10 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11919908B2 (en) 2020-12-21 2024-03-05 Incyte Corporation Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors
US11958861B2 (en) 2021-02-25 2024-04-16 Incyte Corporation Spirocyclic lactams as JAK2 V617F inhibitors

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BR0313724A (pt) 2005-06-28
US6977261B2 (en) 2005-12-20
US20040038961A1 (en) 2004-02-26
CA2495293A1 (fr) 2004-02-19
JP2006504665A (ja) 2006-02-09
AU2003249531A1 (en) 2004-02-25
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